DE1445655C3 - Process for the preparation of 3,4,5,6-tetrahydropyridine derivatives containing gamma-aminopropyl groups in the 3-position - Google Patents

Description

a) ammonia or

b) a small amount of a strongly alkaline compound or

c) a small amount of phenol or dihydroxybenzenes or

d) ammonia and a small amount of a strongly alkaline compound or

e) ammonia and a small amount of phenol or a dihydroxybenzene

implements.

2. The method according to claim 1, characterized in that one carries out the reaction in a temperature range of 80 to 130 ⁰ C.

The invention relates to a process for the preparation of 3,4,5,6-tetrahydropyridine derivatives containing γ-aminopropyl groups in the 3-position, which process is characterized in that ketones which have at least two / 3-cyanoethyl groups in the α-position to the keto group are used , in the presence of hydrogenation catalysts with hydrogen at temperatures between 40 and 180 ⁰ C, pressures below 150 atü and in the presence of

a) ammonia or

b) a small amount of a strongly alkaline compound or

c) a small amount of phenol or dihydroxybenzene or

d) ammonia and a small amount of a strongly alkaline compound or

e) ammonia and a small amount of phenol or a dihydroxybenzene

implements.

It is known that nitriles which have a carbonyl group in the ό-position to the nitrile group can be converted into substituted piperidine derivatives by hydrogenation. So z. B. according to NF A 1 berts ο η (J. Am. Former Soc, 72, pp. 2594 to 2599 [1950]) from 3,3-bis- (/ 3-cyanoethyl) -butanone- (2) 2, 3-dimethyl - 3 - (γ - aminopropyl) - piperidine. The formation of piperidine derivatives can be explained by the fact that an amino group formed from the nitrile group by hydrogenation reacts with the carbonyl group with elimination of water and that the carbon-nitrogen double bond formed is further hydrogenated.

Piperidine derivatives are according to Houbcn

We yl. Methods of Organic Chemistry, 4th Edition, Vol. XI, 1, p. 358 (1957) formed from such compounds in which an amino group by reduction in ('i-position to the carbonyl group can.

From Ber., 82 (1949), pp. 105 to 112, and DT-PS 9 04 532 are theoretically possible reaction processes the catalytic hydrogenation of derivatives of l-cyano-pentanone- (4) or of 4-amino-l-cyano-pentane known. The teaching given there, however, relates only to simply cyanoethylated ketones.

In contrast to the information in the literature, it has now surprisingly been found that γ-cyan ketones with at least 2β-cyanoethyl groups in -position to the keto group with good yield to 3,4,5,6-tetrahydropyridine derivatives let it hydrate. The hydrogenation to the tetrahydropyridine derivatives surprisingly proceeds so smoothly that after absorption of the No further measures are required to reduce the hydrogen required for nitrile groups, about the uptake of a further mole of hydrogen for the hydrogenation of those formed by condensation Prevent carbon-nitrogen double bond. After the hydrogen uptake has ceased Tetrahydropyridine derivatives are present, which in addition to the secondary and tertiary ones that are usually obtained Amines contain only small amounts of the respective piperidine derivative. .

The formation of 3,4,5,6-tetrahydropyridine derivatives in predominant amount is due to both Elemental analysis as well as infrared spectrum to be regarded as secured.

The hydrogenation of the γ-cyan ketones according to the invention Process is expedient in solvents such as aliphatic alcohols or aliphatic or cyclic ethers, and carried out in the presence of hydrogenation catalysts. The hydrogenation surprisingly runs well even in water.

As hydrogenation catalysts, for. B. Raney nickel, Raney cobalt or nickel applied to carrier substances can be used. Are-depending on the activity of the catalyst, the hydrogenation at temperatures of 40 to 18O ⁰ C performed .: Particularly favorable results are obtained by hydrogenation in the range of 80 to 130 ⁰ C. As a rule, the hydrogen pressure should be below 150 atmospheres. Hydrogenation is preferably carried out in the pressure range: between 5 and 100 atmospheres.

As is well known in the hydrogenation of nitriles! besides primary amines also a more or less! If a large proportion of condensed secondary or tertiary amines is formed, it is advisable to: carry out the hydrogenation in the presence of ammonia in the process according to the invention. Similarly, ^one as an addition of ammonia, an addition of small amounts has a strong basic reaction encryption | bindings, such as B. of alkali hydroxides, alkali; alcoholates or quaternary ammonium bases. The hydrogenation in the presence of; Ammonia and the said alkaline compounds; fertilize proven. A hydrogenation in the vicinity of ammonia with the addition of very small amounts of ammonia has proven to be particularly favorable both in terms of yield and the rate of hydrogenation. Quantities of monohydric or polyhydric phenols have been proven, as can be seen from the following table: '1

Hydrogenation of l, l, l-tris - (/; - cyanoethyl) propane (2) in methanol in the presence of various additions

Catalyst: nickel on kieselguhr

additive % Yield in
2-methy! -3,3-to-
(; -; iminopropyl) -
3,4,5,6-tetra-
hydropyridine 54 NH ₃ 61 Na methylate 62 phenol 61 Hydroquinone 66.4 NH ₃ + trimethyl-benzylammonium-
hydroxide 76 NH ₃ + Na methylate 78.8 NH ₃ + hydroquinone 82.5 As starting materials for the Hvdrier us after the '

Processes according to the invention are primarily compounds from the group of cyanoethylation products of aliphatic, cycloaliphatic or aliphatic-aromatic ketones with at least two β-cyanoethyl groups, such as 1,1-bis- (β-cyanoethyl) propanone- (2), 1 , 1,1 -Tris- (ß-cyanoethyl) -propanon - (2), 2,2 - bis - (ß - cyanoethyl) - butanone - (3), 2 - methyl - 3,3 - bis - (ß - cyanoethyl) - pentene - (1) - on - (4) and c ^ o ^ fi ^ -Tris-i / J-cyanäthylJ-acetophenon.

The tetrahydropyridine derivatives obtainable by the process according to the invention are valuable Intermediate products for the manufacture of pharmaceuticals and vulcanization accelerators.

example 1

A mixture of 150 g of l, l, l-tris (/ f-cyanoethyl) propanone (2) and 600 ml of ammonia-saturated methanol was hydrogenated in the presence of 20 g of a nickel catalyst under a hydrogen pressure of 50 atm at 100 to 115 ° C . The uptake of hydrogen was complete in 40 minutes. After filtering off the catalyst and evaporation of the solvent, 89 g or 61% of theory 2 - methyl - 3,3 - bis - (γ - aminopropyl) -3,4,5,6-tetrahydropyridine were obtained _{by vacuum distillation, bp 01 torr} : 120 up to 135 ⁰ C.

ι B e i s ρ i e 1 2

A mixture of 150 g of l, l, l-tris (β-cyanoethyl) propanone (2), 600 ml of methanol and 1 g of sodium methylate was hydrogenated under the conditions given in Example 1. 91 g or 62.3% of theory of 2 - methyl - 3,3 - bis - (γ - aminopropyl) - 3,4,5,6-tetrahydropyridine were obtained. The boiling point of the product obtained in this way corresponded to the value given in Example 1.

Example 3

A mixture of 150g l, l, l-Tris- (ß-cyanoethyl) -propanon- (2), 600 ml of methanol and 0.3 g of phenol were prepared under the conditions given in Example 1 hydrogenated. There were 89 g or 61% of theory 2 - methyl - 3,3 - bis - (; · - aminopropyl) - 3,4,5,6 - tetrahydropyridine receive. The boiling point of the product obtained in this way corresponded to that in Example 1 specified value.

Example 4

A mixture of 150 g of l, l, l-tris (/ 7-cyanoethyl) propanone (2), 600 ml of methanol and 0.1 g of hydroquinone was hydrogenated under the conditions given in Example 1. 97 g or 66.4% of theory of 2 - methyl - 3,3 - bis - (γ - aminopropyl) -3,4,5,6-tetrahydropyridine were obtained. The boiling point of the product obtained in this way corresponded to the value given in Example 1.

Example 5

A mixture of 150g l, l, l-tris - (/; - cyanoethyl) propanone (2), 600 ml ammonia-saturated methanol and 1 g sodium methylate was in the presence of the nickel catalyst used in Example 1 under a hydrogen pressure of 30 atm 90 to 100 ° C hydrogenated. The yield of 2-methyl-3,3-bis- (γ- aminopropyl) -3,4,5,6-tetrahydropyridine was 115 g = 78.8% of theory. The boiling point of the product obtained in this way corresponded to the value given in Example 1.

Example 6

As in Example 5. Instead of 1 g of sodium methylate, however, 4 ml of a 30% strength methanolic solution were used related to trimethylbenzylammonium hydroxide.

The yield of 2-methyl-3,3-bis - (> '- aminopropyl) -3,4,5,6-tetrahydropyridine was 11Ig = 76% of theory. The boiling point of the product obtained in this way corresponded to the value given in example 1. ,.

Example 7

A mixture of 200g l, l, l-tris - (/ 7-cyanoethyl) propanone- (2), 800 ml ammonia-saturated methanol and 0.1 g hydroquinone was in the presence of the nickel catalyst used in Example 1 under a hydrogen pressure of 50atü hydrogenated at 100 to 115 ⁰ C. The yield of 2-methyl-3,3-bis (γ-aminopropyl) -3,4,5,6-tetrahydropyridine was 160 g = 82.5% of theory. The boiling point of the product obtained in this way corresponded to the value given in Example 1.

Example 8

In an autoclave, a solution of 90 g of 3,3-bis (p'-cyanoethyl) butanone (2), 73 g of ammonia and

'"0.5 g of sodium in 400 ml of methanol in the presence of 10 g of Raney nickel at a hydrogen pressure of Maintained 130 atü for 80 minutes at a temperature of 100 ° C. After cooling it became the catalyst filtered off, methanol and ammonia evaporated under normal pressure and the residue at Distilled water jet vacuum.

There were obtained at 110 to 125 Kp _nTorr ^Ü C to 77 g (90% of theory) of water clear liquid, from the pure by fractional distillation 2.3 -. Dimethyl - 3 - (γ - aminopropyl) - 3,4, 5,6 - tetrahydropyridine with a _{boiling point of} 111 to 113 ° C. could be separated off in 70% yield.

This compound solidified after prolonged standing at 16 to 18 ^C C to form crystals that dissolve in air. nl ' 1.5050.

C ₁₀ H ₂₀ N ₂ (molecular weight 168.3):
Calculated:

C 71.37, H 11.98, N 16.65,

Nnh ₂ according to van SI yke 16.65%; _s

found:

C 71.54, H 11.81, N 16.92,
Nnh ₂ according to van S 1 yke 16.11%.

Dihydrochloride: colorless crystals, m.p. 248 to 249 ° C. o

C ₁₀ H ₂₂ N ₂ Cl ₂ (molecular weight 241.2): Calculated:

C 49.79, H 9.19, N 11.61, Cl 29.40%; found:

C 49.80, H 8.99, N 11.55, Cl 29.42.

The higher-boiling fractions (b.p. _torr 114 to 125 ° C) contain larger amounts of 2,3-dimethyl-3- (v-aminopropyl) -pipendin with increasing boiling point.

If no metallic sodium is added to the reaction mixture for hydrogenation, the yields are low of crude distillate only about 60% compared to 90% in the case of a hydrogenation in the presence of sodium.

Example 9

A mixture of 90 g of 2-methyl-3,3-bis - (/; - cyanoethyl) -pentene- (l) -one- (4), 1 g of sodium methylate and 500 ml of ammonia-saturated methanol was added with 15 g of Raney nickel hydrogenated at 80 to 100'C under a hydrogen pressure of 100 atm. The uptake of hydrogen ceased after 45 minutes. The reaction solution was separated from the catalyst by filtration, the solvent was evaporated and the oily residue was distilled in vacuo. The 2-methyl-3-isopropenyl-3 - ( '- aminopropyl) -3,4,5,6-tetrahydropyridine boiling at 100 to 110 ^r' C / 0, l tone The yield was 73 g = 84.5 % of theory.

Q ₂ H ₂₂ N ₂ (molecular weight 194.3):

Calculated:

C 74.17, H 11.41, N 14.42,

NnH ₂ according to van S 1 yke 14.42%; found:

C 74.11, H 11.56, N 14.33,

Nnh ₂ according to van SI yke 14.13%.

Example 10

A suspension of 800 g of 1,1,1 -tris (p'-cyanoethyl) -propanon- (2) in 4 L of water was in the presence of 100 g of a nickel catalyst under a hydrogen pressure of 30atü at 80 to 100 ⁰ C was hydrogenated. The uptake of hydrogen ceased after 20 minutes. After filtering off the catalyst and evaporation of the water, a pale yellowish oily liquid remained, which for the most part consisted of 2-methyl-3,3 - bis - (; '- aminopropyl) - 3,4,5,6 - tetrahydropyridine.

Example 11
The following were placed in a stirred autoclave:

i'Vv »-Tris- (β-cyanoethyl) -acetophenone 56 g

Met. Sodium, dissolved in 500 ml
Section. Methanol with a content
from 5 g of NH ₃ 0.4 g

Nickel catalyst 7 g

_{NH 3} was first injected onto this mixture at a pressure of 5 atmospheres, then hydrogen at 135 atmospheres. The hydrogenation temperature was 105 ⁰ C, the hydrogenation time 120 minutes. Within the first 20 minutes, the pressure decreased by 35 atm, whereupon hydrogen was again injected to 135 atm. The final pressure was 100 atm. The methanolic solution was separated from the catalyst. After removing NH ₃ and methanol, the light green colored reaction product was distilled in vacuo. The crude distillation gives 38 g of a distillate of Kp-Oi _-0 I ₅₇ Or ₁ -ISO up to 215 ° C., from which 32 g of pure 2-phenyl-3,3-bis (γ-aminopropyl) -3 are obtained by fine fractionation , 4,5,6-tetrahydropyridine with a bp. ₀ , i_o.i5Torr 193 to 194 ° C were obtained. Yield: 59% of theory.) !!, ⁰ = 1.5659.

C ₁₇ H ₂₇ N ₃ (molecular weight 271.3):

Calculated:

N 15.48, Nnh ₂ (according to van S 1 yke) 15.48%;
found:

N 15.61, Nnh ₂ (according to van S 1 y ke) 15.30%.

Claims (1)

Patent claims: 1. A process for the preparation of 3,4,5,6-tetrahydropyridine derivatives containing y-aminopropyl groups in the 3-position, characterized in that ketones which have at least two β-cyanoethyl groups in the u-position to the keto group are used in the presence of hydrogenation catalysts Hydrogen at temperatures between 40 and 180 ⁰ C, pressures below 150atii and in the presence of