DE19852282A1 - Racemization of optically active amines useful as pharmaceuticals or intermediates, by contacting in gaseous form with hydrogen and catalyst, giving high racemization degree and yield - Google Patents

Abstract

The racemization of optically active, optionally substituted aliphatic secondary amines (I) by contacting with hydrogen and a (de)hydrogenation catalyst is carried out in the gas phase. Racemization of optically active amines (I) involves contacting (I), in the gas phase, with hydrogen and a hydrogenation or dehydrogenation catalyst at elevated temperatures. R1 = H, alkyl, cycloalkyl, aralkyl, aryl, heteroaryl or heterocyclyl (all optionally substituted by alkyl, cycloalkyl, alkoxy, aryloxy, alkylamino or dialkylamino); with the proviso that R1 and R2 are different. R2, R3 = alkyl, cycloalkyl, aralkyl, aryl, heteroaryl or heterocyclyl (all optionally substituted by alkyl, cycloalkyl, alkoxy, aryloxy, alkylamino or dialkylamino);

Description

The present invention relates to a process for the racemization of optically active amines of the formula (I)

in which R ¹ , R ² and R ^{3 are} alkyl, cycloalkyl, arylalkyl, aryl, heteroaryl and heterocyclic radicals and R ^{3 is} additional H, wherein the radicals are substituted by substituents selected from the group alkyl, cycloalkyl, alkoxy , Aryloxy, alkylamino and dialkylamino, with the proviso that R ¹ and R ^{2 are} different, by reacting the optically active amine in the presence of hydrogen and a hydrogenation or dehydrogenation catalyst at elevated temperature.

Optically active amines of the formula I are z. B. valuable Pharmazeu tika and intermediates for the production of active substances (cf. z. B .: DE-A-29 03 589, page 2, lines 17 to 26). As often only one of the two enantiomers is effective, or more effective than that other enantiomer is, are processes for the racemization of the we niger effective enantiomer needed because of the racemate known methods (resolution) again the more effective Enantiomer can be obtained.

US-A-4,096,186 describes a process for the racemization of op table-active aminoalcohols, wherein the aminoalcohol with ammonia and hydrogen in the presence of a hydrogenation catalyst, the preferably contains cobalt, is brought into contact. At the Um tion of optically active 2-amino-1-butanol is at a Ra Cematausbeute of a maximum of 97.6%, only one Racemisierungsgrad of 63% achieved. At a racemization level of 99% is against only reached a racemate yield of 75.1%.

US-A-4,990,666 discloses a process for the racemization of op table-active aminoalcohols, wherein the aminoalcohol in the presence of hydrogen is contacted with Raney cobalt. It it is taught that high temperatures, e.g. B. greater than 160 ° C, the Ra Minimize cemat yield. Furthermore, according to this doctrine Racemization in the liquid phase in the presence of an inert Solvent.  

DE-A-29 03 589 describes a process for the preparation of race mixtures of optically active amines by mixing the op table active amines with hydrogen in the presence of a hydrogenation treated catalyst at elevated temperature. It is taught the racemization of the optically active amine, depending on the nature purity of the amine, in solvents or in substance, d. H. in liquid or solid form. The implementation of op active 2-amino-1-phenylpropane in the liquid phase in a Reaction time of 12 hours on a Raney cobalt catalyst At a racemization level of at most 98% only leads to one Racemate yield of 91.1%.

The present invention has the object, a verbes sertes economical process for the racemization of optically to find active amines in which the process product with ho hem racemization degree with simultaneous high racemization prey and high space-time yield is obtained.

Accordingly, a process for the racemization of optically active amines of the formula (I)

in which R ¹ , R ² and R ^{3 are} alkyl, cycloalkyl, arylalkyl, aryl, heteroaryl and heterocyclic radicals and R ^{3 is} additional H, wherein the radicals are substituted by substituents selected from the group alkyl, cycloalkyl, alkoxy , Aryloxy, alkylamino and dialkylamino, with the proviso that R ¹ and R ^{2 are} different, found by reacting the optically active amine in the presence of hydrogen and a hydrogenation or dehydrogenation catalyst at elevated temperature, thereby characterized is that one carries out the reaction in the gas phase.

The inventive method can be carried out in the gas phase diskon continuously or preferably continuously as follows, wherein the catalyst is preferably angeord net as a fixed bed in the reactor:
The process according to the invention can be carried out in the absence or preferably in the presence of ammonia. If the reaction is carried out in the presence of ammonia, the molar ratio of ammonia to amine (I) is generally 1: 1 to 50: 1, preferably 1.5: 1 to 30: 1, particularly preferably 2: 1 to 20: 1, very particularly preferably 2: 1 to 6: 1. The excess of ammonia, based on the amine (I), can also be greater than 50: 1.

The hydrogen generally becomes available to the reaction in an amount from 5 to 400 l, preferably in an amount of 50 to 200 l per Mol amine component fed, the liter data each on Normal conditions are converted (S.T. P.).

The amine (I) is in a sufficiently large for evaporation ge selected gas stream containing hydrogen and optionally ammonia, preferably consisting of hydrogen and optionally ammonia, at pressures of 0.1 to 30 MPa, preferably 0.1 to 5 MPa, especially preferably 0.1 to 3 MPa, and temperatures of 100 to 300 ° C, preferably 150 to 270 ° C, more preferably 180 to 250 ° C, passed in gaseous form over the catalyst. It is both an influx of the fixed catalyst bed from above and from below possible. The required gas stream is preferably obtained by a cycle gas method, for example, at a Ka talysatorschüttvolumen of 1 l a circulating gas of about 5 to 10 m ³ / h (volume converted to normal conditions) and an exhaust gas amount of about 250 to 350 l / h becomes. The catalyst loading is generally in the range of 0.1 to 2, preferably 0.1 to 1, more preferably 0.2 to 0.6 kg of amine (I) per liter of catalyst (bulk volume) and hour.

The application of higher temperatures, higher total pressures as well higher catalyst loads than stated above is possible. The pressure in the reaction vessel, which consists essentially of the Sum of the partial pressures of the amine component (I), of the given if existing ammonia and the formed racemized Amines at each applied temperature results will be appropriate moderately by pressing hydrogen to the desired Reaction pressure increased.

The hydrogen can be used together with the optionally used Ammonia are circulated.

From the reaction, after this expediently has been relaxed, the hydrogen and possibly used Ammonia removed and the resulting cooled Reaktionsrohpro which essentially contains the racemic amine (I) a fractionating rectification, if necessary in verminder tem pressure, cleaned.

With regard to the usable in the process according to the invention Hydrogenation catalysts and dehydrogenation catalysts are not an to make restrictions.  

As hydrogenation catalysts and dehydrogenation catalysts are Catalysts comprising copper, silver, gold, iron, cobalt, nickel, Rhenium, ruthenium, rhodium, palladium, osmium, iridium, platinum, Chromium, molybdenum, tungsten or mixtures thereof, suitable. Suitable catalysts are, for example, supported catalysts, which are preferably arranged in the reactor as a fixed bed and after the person skilled in known methods (precipitation methods, impregnation Me methods).

In the supported catalysts come as a carrier material for the ka talytically active metals or metal compounds, eg. Metal oxides, for example carbon, alumina, silica, Titanium dioxide, zirconium dioxide, zinc oxide, magnesium oxide, silicon carbide, zeolites or mixtures thereof, into consideration.

For example, supported catalysts which are copper and / or co balt and / or nickel and alumina and / or zirconia and / or or titanium dioxide, to run.

For example, supported catalysts of the composition
76 wt .-% Al, calculated as Al ₂ O ₃ , 4 wt .-% Cu, calculated as CuO, 10 wt .-% Co, calculated as CoO and 10 wt .-% Ni, calculated as NiO, (according to DE -A-19 53 263)
and
31.5% by weight Zr, calculated as ZrO ₂ , 50% by weight Ni, calculated as NiO, 17% by weight Cu, calculated as CuO and 1.5% Mo, calculated as MoO ₃ , (according to EP -A-696 572)
and the copper-containing precipitation catalyst disclosed in DE-A-24 45 303, Example 1, which is prepared by treating a solution of copper nitrate and aluminum nitrate with sodium bicarbonate and subsequently washing, drying and annealing the precipitate, in the process of the present invention.

In the process according to the invention, preference is given to catalysts whose catalytically active composition prior to reduction with hydrogen contains 20 to 85% by weight, preferably 40 to 80% by weight, of oxygen-containing compounds of aluminum, calculated as Al ₂ O ₃ , oxygen-containing compounds of zirconium calculated as ZrO ₂ , and / or oxygen-containing compounds of titanium, calculated as TiO ₂ , 1 to 70 wt .-%, preferably 20 to 60 wt .-%, oxygen-containing compounds of copper, calculated as CuO, and 0 to 50 wt .-% oxygen-containing compounds of magnesium, calculated as MgO, oxygen-containing compounds of chromium, calculated as Cr ₂ O ₃ , oxygen-containing compounds of zinc, calculated as ZnO, and / or oxygen-containing compounds of calcium, calculated as CaO, contains used.

The radicals R ¹ , R ² and R ^{3 of} the in the process according to the invention set optically active amines of the formula (I)

independently represent alkyl, cycloalkyl, arylalkyl, aryl, heteroaryl and heterocyclic radicals and R ³ additionally H, wherein the radicals by inert under the reaction conditions substituents selected from the group alkyl, cycloalkyl, alkoxy, aryloxy, alkylamino and dialkylamino , and wherein furthermore R ¹ and R ^{2 are} different.

R ¹ , R ² and R ³ preferably mean:

• a linear or branched alkyl radical, such as C _1-20 -alkyl, particularly preferably C _1-12 -alkyl, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, iso-pentyl, sec-pentyl, neo-pentyl, 1, 2-dimethylpropyl, n-hexyl, iso-hexyl, sec-hexyl, cyclopentylmethyl, n-heptyl, iso- Heptyl, cyclohexylmethyl, n-octyl, 2-ethyl-hexyl, n-nyl, iso-nonyl, n-decyl, iso-decyl, n-undecyl, n-dodecyl, iso-dodecyl,
  most preferably C _1-8 alkyl, such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl and 2-ethyl-hexyl.
• Cycloalkyl radical, preferably C _3-8 -cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl, particularly preferably cyclopentyl, cyclohexyl and cyclooctyl,
  very particularly preferably cyclopentyl and cyclohexyl,
• - Arylalkylrest, preferably C _7-20 arylalkyl, such as benzyl, 1-phen ethyl, 2-phenethyl, 1-naphthylmethyl, 2-naphthylmethyl, Phe nanthrylmethyle, 4-tert-butyl-phenyl-methyl, 1-phenylpropyl, 2 Phenylpropyl, 3-phenylpropyl, 1-phenylbutyl, 2-phenylbutyl, 3-phenylbutyl and 4-phenylbutyl,
  particularly preferably benzyl, 1-phenethyl and 2-phenethyl,
• - Aromatic radical, preferably C _6-20 aryl, such as phenyl, 1-naphthyl, 2-naphthyl, 1-anthryl, 2-anthryl, 9-anthryl, be particularly preferably phenyl, 1-naphthyl and 2-naphthyl, FITS preferably phenyl,
• heteroaromatic radical, preferably C _3-15 heteroaryl, such as 2-pyridinyl, 3-pyridinyl, 4-pyridinyl, quinolinyl, pyrazinyl, pyrrol-3-yl, thienyl, imidazol-2-yl, 2-furanyl and 3-furanyl , and
• heterocyclic radical, preferably C _3-15 -heterocycloalkyl, such as N-alkyl-piperidin-3-yl, N-alkyl-piperidin-4-yl, N, N'-dialkyl-piperazin-2-yl, tetrahydrofuran-3-yl and N-alkylpyrrolinedin-3-yl,

in which case the radical R may carry inert substituents under the reaction conditions, such as, for example, Eg C _1-20

Alkyl, C _3-8

-Cycloalkyl, C _1-20

Alkoxy, C _6-20

-Aryloxy, C _1-20

Alkylamino and C _2-20

Dialkylamino.

The number of these substituents in R can be 0 to 5, preferably 0 to 3, in particular 0, 1 or 2, depending on the nature of the radical. Particularly suitable substituents are:

• C _1-20 -alkyl, as defined above,
• C _3-8 -cycloalkyl, as defined above,
• C _1-20 -alkoxy, preferably C _1-8 -alkoxy, such as methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy, n-pentoxy iso-pentoxy, sec-pentoxy, neo-pentoxy, 1,2-dimethylpropoxy, n-hexoxy, iso-hexoxy, sec-hexoxy, n-heptoxy, iso-heptoxy, n-octoxy, iso-octoxy,
  particularly preferably C ₁₄ -alkoxy, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy and tert-butoxy,
• C _6-20 -aryloxy, such as phenoxy, 1-naphthoxy and 2-naphthoxy, preferably phenoxy,
• C _2-20 dialkylamino, preferably C _2-12 dialkylamino, especially C _2-8 dialkylamino, such as N, N-dimethylamino, N, N -diethylamino, N, N-di-n-propylamino, N, N Di-iso-propylamino, N, N-di-n-butylamino, N-ethyl-N-methylamino, N-methyl-N-propylamino, dicyclohexylamino, and
• C _1-20 -alkylamino, preferably C _1-12 -alkylamino, especially C _1-8 -alkylamino, such as methylamino, ethylamino, n-propylamino, isopropylamino, n-butylamino, isobutylamino, tert-butylamino , Cyclopentylamino, cyclohexylamino.

R ³ is very particularly preferably hydrogen (H).

Examples of amines I which can be used in the process according to the invention are:
1-methoxy-2-aminopropane (MOIPA), 2-amino-3-methyl-butane, 2-amino-3, 3-dimethylbutane, 1-phenylethylamine, 1-naphthylethylamine, min. 2-naphthylethylamine, 1-pherylpropylamine, 1- (4-methylphenyl) ethylamine, 1- (4-methoxyphenyl) ethylamine, 1- (3-methoxy-phenyl) -ethylamine, 1-aminotetralin, trans-1-amino-2-benzyloxy -cyclopentane and trans-1-amino-2-benzyloxy-cyclohexane.

Particularly preferred are 1-methoxy-2-aminopropane, 2-amino-3-me thyl-butane and 2-amino-3,3-dimethylbutane.

Examples Comparative Example 1 Attempt to racemize (R) -MOIPA analogous to DE-A-29 03 589

10 g of (R) -mOIPA (112 mmol), 70 ml of tetrahydrofuran and 1 g of Raney cobalt were placed in a 0.3 liter autoclave. With hydrogen, a pressure of 20 bar was set. The autoclave was heated to 160 ° C and the H ₂ pressure increased to 50 bar. After 12 h under these conditions was cooled to room temperature, the catalyst was filtered off and the tetrahydrofuran removed on Rotationsver evaporator. The amount of residue was 2.5 g.

Determination of enantiomeric excess by HPLC analysis: 4.8%
(S) -MOIPA = 47.6 F1.%
(R) -MOIPA = 52.4 Fl.%

GC analysis [Fl.%]:

tetrahydrofuran 0.2 methoxyisopropanol 2.2 MOIPA 68.3 octylamine 3.7 octanol 10.0 Total unknown verb 15.6 racemization 90% racemate 61%

Comparative Example 2 Attempt to racemize (S) -3,3-dimethyl-2-amino-butane (Pi nacolylamine) analogously to DE-A-29 03 589

10 g of (S) -pinacolylamine (99% ee) were mixed with 60 g of THF and 1 g Raney cobalt mixed in a 0.3 l crude autoclave and under a hydrogen atmosphere at a pressure of 50 bar and a Temperature of 165 ° C for 12 h.

The reactor contents were then cooled to room temperature and separated from the catalyst and the enantiomeric ratio determined via a chiral HPLC column.

Enantiomeric excess: 99%

GC analysis of the effluent (ammonia and anhydrous) in GC fl.%:

pinacolone 0.1 Pinacolylamin 99.2 Pinacolol 0.5 other 0.2 racemization 0% racemate 99.2%

example 1 Racemization of (R) -mOIPA in continuous mode

(R) -1-Methoxyisopropylamin ((R) -MOIPA) was driven together with ammonia and hydrogen via a preheater in the operated at 15 bar overpressure reactor. The reactor had a temperature of 190 to 210 ° C; the circulating gas amount was about 7 Nm ³ / (l _cat .. h). It was a small amount of exhaust gas of 300 Nl / (l _Kat .. h) driven.

The reactor was filled with a precipitation catalyst having the composition 45% by weight of CuO, 10% by weight of NiO and 45% by weight of y-Al ₂ O _{3 support} . Before the start of the reaction, the catalyst was reduced in a hydrogen stream at 240 ° C. The molar ratio R-NIOIPA to ammonia was 1: 6, the catalyst loading was 0.3 kg (R) -MOIPA and 0.29 kg ammonia per liter of catalyst per hour.

The Ofenaustrag was relaxed in a separator and worked up by distillation.

GC analysis of the effluent (ammonia and anhydrous) in GC fl.%:

(R / S) -MOIPA 92.5 [(R) -MOIPA: (S) -MOIPA = 50.3: 49.7] methanol 0.3 isopropylamine 0.6 methoxyisopropanol 1.1 octylamine 2.1 octanol 0.2 other 3.2 racemization: 99 racemate: 92

Example 2 Racemization of (S) -pinacoline (2-amino-3,3-dimethylbutane) in continuous driving style

Pinacolylamine (90% S enantiomer, 10% pinacolone) was combined with ammonia and hydrogen through a static mixer and Preheater in a reactor operated at atmospheric pressure ge drive (temp .: 160 to 200 ° C, straight passage). The reactor was with catalyst (see below for composition), e.g. B. 3 × 3 mm tablet th, filled. The Ofenaustrag was condensed and in addition Product caught in a cold trap. The analysis was carried out on hand chiral HPLC.

The results are summarized in Table 1.

Table 1

Vorheiztemp. exit 201 ° C Reaktortemp. entrance 200 ° C Reaktortemp. exit 201 ° C AL = L <feed: reactant 16 ml / h H ₂ 37 l / h NH ₃ 16 l / h reactor volume 110 ml

Claims (7)

1. Process for the racemization of optically active amines of the formula (I)
in which R ¹ , R ² and R ^{3 are} alkyl, cycloalkyl, arylalkyl, aryl, heteroaryl radicals and heterocyclic radicals and R ³ is additionally H, the radicals being substituted by substituents selected from the group consisting of alkyl, cycloalkyl, alkoxy , Aryloxy, alkylamino and dialkylamino, with the proviso that R ¹ and R ^{2 are} different, by reacting the optically active amine in the presence of hydrogen and a hydrogenation or dehydrogenation catalyst at elevated temperature, characterized in that the Implementation in the gas phase. 2. The method according to claim 1, characterized in that one the reaction is carried out at temperatures of 150 to 270 ° C. 3. The method according to claim 1, characterized in that one the reaction is carried out at temperatures of 180 to 250 ° C. 4. Process according to claims 1 to 3, characterized gekennzeich net, that the reaction at pressures of 0.1 to 5 MPa performs. 5. Process according to claims 1 to 4, characterized in that a catalyst whose catalytically active composition before reduction with hydrogen
20 to 85% by weight of oxygen-containing compounds of the aluminum, calculated as Al ₂ O ₃ , of oxygen-containing compounds of zirconium, calculated as ZrO ₂ , and / or of oxygen-containing compounds of titanium, calculated as TiO ₂ ,
1 to 70 wt .-% oxygen-containing compounds of copper, calculated as CuO, and
0 to 50 wt .-% oxygen-containing compounds of magnesium, calculated as MgO, oxygen-containing compounds of chromium, calculated as Cr ₂ O ₃ , oxygen-containing compounds of zinc, calculated as ZnO, and / or oxygen-containing compounds of calcium, calculated as CaO, contains, uses. 6. Process according to claims 1 to 5, characterized gekennzeich net, that the reaction in the presence of ammonia through leads. 7. Process according to claims 1 to 6, characterized gekennzeich net, that is as optically active amine 1-methoxy-2-amino propane, 2-amino-3-methyl-butane or 2-amino-3,3-dimethylbutane starts.