DD204081B1 - PROCESS FOR THE PREPARATION OF ALPHA-HYDROXYKETIMINES AND THEIR SALTS - Google Patents

Description

in which R ₂ to R _{4 have} the abovementioned meaning, with amines of the general formula R ₁ -NH ₂ , III,

wherein Ri has the abovementioned meaning, at temperatures between room temperature and elevated temperature, characterized in that the a-hydroxy ketones of the general formula II with aqueous solutions of amines of the general formula III in the presence of a solvent at temperatures between 20 ⁰ C and 70 ⁰ C converts.

2. The method according to claim 1, characterized in that one uses methanol or ethanol as the solvent.

3. Process according to claims 1 and 2, characterized in that per mole of a-hydroxy ketone of the general formula II 1 to 3 moles of amine of general formula III is used.

Field of application of the invention

The invention relates to a process for the preparation of α-hydroxyketimines of the general formula

C - C - у / _lf

R.

4 OH NO

in the R _{1 is} hydrogen or a lower alkyl group having 1 to 2 C atoms, R _{2 is} hydrogen or chlorine and R ₃ and R _{4 are} each a methyl group or R ₃ and R ₄ together with the C-atom to which they are attached, a cyclopentyl group, and their salts with inorganic acids.

Such a-hydroxyketimines are valuable intermediates in the drug industry.

By thermal rearrangement, they can be converted into α-aminoketones, which exert a strong effect on the central nervous system and thus represent highly effective drugs.

Characteristic of the known technical solutions

It is known to prepare α-hydroxyketimines by reacting α-bromoketones, α-hydroxyketones or their ketals with amines according to the following formula scheme:

OCH

C-C-

Ч Br 0

R ₁ -:

 нн.

: σ - σ -

 4 ОН

R ₁ -HH,

σ-σI il

он ο

In these formulas, R ₁ to R _{4 have} the abovementioned meaning

Thus, a-bromoketones at temperatures between -60 ⁰ C and -30 ⁰ C with liquid ammonia or liquefied aliphatic amines to convert a-hydroxyketimines (GB PS 1202834, DE-AS 1293761, J Amer Chem Soc 95 [1973], 1978 ) The temperatures required for the reaction in the desired sense can be achieved under laboratory conditions by cooling with dry ice, but on an industrial scale they are difficult to implement. This is a major disadvantage of this procedure

However, if the reaction is allowed to proceed at elevated temperatures or in solvents, the unwanted a-aminoketones or mixtures of the two isomeric compounds, which are virtually indistinguishable, are obtained instead of the desired a-hydroxyketimme (J Amer Chem Soc 95 [1973], 1978 )

Solv.

increased

temperature

Attempts have been made to circumvent the low temperatures by first converting the α-bromoketones with equivalent amounts of methanolic Natriummethylatlosung in a ketal of the corresponding α-hydroxy ketone and then reacted with an amine to a-hydroxyketimine

For example, 2-methoxy-2-phenyl-2-oxaspiro [2,4] heptane was reacted with toluidine to give 1- (ap-tolyliminobenzyl) -cyclopentanol. For this, it was necessary to heat at 110 ° C for 30 minutes The methanol formed in the reaction simultaneously distill off under reduced pressure (J Org Chem 30 [1965], 2962). However, this process is limited to heavy-volatility amines such as toluidine

In order to implement the ketals with slightly volatile amines, such as methylamine, has been used in autoclaves under pressure This procedure, however, led to the isomeric aminoketones (DE-AS 1293761 see Example 2 last section) and is thus useless

It is also known, a-hydroxyketones in a-Hydroxyketimine to be traveled by these react with amines either at room temperature in a closed vessel for several days or at temperatures of about 100 ⁰ C for several hours to several days in an autoclave let An addition of potash or caustic soda it should shorten the reaction time (DE-AS 1293761, J Amer Chem Soc 85 [1963], 1464, ibid 88 [1966], 2769, J Org Chem 30 [1965], 2967, ibid 31 [1966], 2593 and 2601, ibid 37 [1972], 2091, J Amer Chem Soc 95 [1973], 1978)

In these processes, one must work with a large excess of amine, which must be collected after completion of the reaction. In terms of environmental protection, such a procedure is associated with an additional technical effort

The hitherto known technical solutions for the preparation of α-hydroxyketimines thus require the generation of low temperatures or pressure reactions, are associated with long reaction times and with great effort to absorb and recover the amines, or lead to the simultaneous formation of the undesired isomeric a-amino ketones also In all known technical solutions, the a-hydroxyketimines are unclean. There is no need for a simple process for obtaining a-hydroxyketimines

Object of the invention

The invention makes it possible to produce a-hydroxyketimines of the general formula I technically easily and in reasonable reaction times without pressure, without causing low temperatures must be generated and the amount of amines used is kept within such limits that a recovery is not required a-Hydroxyketimine accumulate in high yields and excellent quality, so that they do not need to be cleaned before further processing

-ex- 204 081 Explanation of the essence of the invention

The present invention has as its object, α-hydroxyketimines of general formula I, in which the radicals R, to R _{4 have} the abovementioned meaning, in good yields and high purity, in reasonable reaction times, while avoiding pressure reactions, without generating deeper According to the present invention, this is achieved by reacting α-hydroxy ketones of the general formula

in which the radicals R ₂ to R _{4 have} the abovementioned meaning in a solvent with an aqueous solution of an amine of the general formula

Ri-NH ₂ III,

in which R _{1 has} the abovementioned meaning, reacted at temperatures between 20 and 70 ⁰ C.

Suitable solvents are lower alcohols, such as methanol or ethanol, methanol being preferred for technical reasons

The amount of the solvent is not limited. For reasons of expediency, it is possible to use 5 to 10 times the amount of alcohol

The molar ratio of the reactants is also variable, but one should use at least one mole of α-hydroxy ketone 1 to 3 moles of the relevant amine

The reaction times are dependent on the reaction conditions chosen and vary between several days at room temperature and 5 to 20 hours at elevated temperature. The progress of the reaction can be followed by a titaniumimetric process. This is a particular advantage of the process according to the invention

The reaction solution can be worked up in various ways. The solution can be poured into 4 to 6 times the amount of water (based on the amount of solvent used) and the resulting a-hydroxyketimine can be aspirated in the formula to reduce the quantities of solvent but also possible to distill the alcohol used as a solvent after completion of the reaction largely and give the residue in the 4- to 6-fold amount of water (based on the volume of the residue) As above, one wins the Hydroxyketimin the general formula I by suction

The yields are consistently above 85% and the α-hydroxyketimines are obtained in such high purity that, if desired, they can be converted directly into their salts. The preparation of the salts from the resulting compounds of the general formula I can be carried out according to known methods Procedure be done in two ways by either the a-hydroxyketimine in the 4- to 6-fold amount of an organic solvent, Tolu B toluene or acetone, lost and hydrogen chloride is introduced to the acidic reaction or treated with an appropriate amount of isopropanolic hydrochloric acid.

The hydrochloride precipitates and can be isolated by suction. Instead of hydrogen chloride or hydrochloric acid, other acids can be used in the same way for salt formation

The use of aqueous solutions of the amine of general formula III is surprising and unforeseeable for the skilled person, since in the reaction of the α-hydroxy ketone with the amine according to the equation

Water is formed as a second reaction product and thus aqueous solutions should shift the balance to the left The inventive method has the following advantages over the known technical solutions

- Instead of the pure liquefied amines the cheap aqueous solutions can be used

- It is not necessary to generate jerk with regard to the low boiling points of the pure nurse for reaction temperatures from -60 to -30 ⁰ C, but it can be carried out at room temperature or easily realizable temperatures between 20 and 70 ⁰ C.

- No autoclave required for the reaction It can be used in simple laboratory flasks, hanging vessels or boilers

- The reaction can be easily controlled by monitoring the amount of amine consumed by titration and followed, the amines need to be used only in slight excess.

The α-hydroxyketimines are so neat that they can be converted into their salts without any intermediate purification and, if appropriate, are suitable for further reactions in this form

embodiments example 1

Dissolve 16.4 g (0.1 mol) of a-hydroxyisopropyl phenyl ketone in 100 ml of methanol and add 15 ml of concentrated ammonia (25%). The solution is stirred for 18 hours at 6O ⁰ C and then poured into 540 ml of water. The a-hydroxyisopropyl phenyl ketone imine precipitates out. It is filtered off with suction, washed with water and dried in air. This gives 14.4 g of 88% of theory, mp 82-84 ° C.

Example 2

8.2 g (0.05 mol) of α-hydroxyisopropyl phenyl ketone in 50 ml of methanol are mixed with 12.5 ml (0.11 mol) of an aqueous ethylamine solution (400 g / l) and allowed to stand for 5 days at room temperature. Then you give the solution in 270ml of ice water. The precipitating Öl.erstarrt after some time. It is filtered off, washed with water and dried in a desiccator.

This gives 17.8 δ 93% of theory α-hydroxyisopropyl phenyl ketone N-ethylimine, mp. 36-37.5 ° C.

Example 3

11.2 g (0.05 mol) of α-hydroxycyclopentyl-o-chlorophenyl ketone are dissolved in 50 ml of methanol and admixed with 10 ml (0.1 mol) of aqueous methylamine solution (content: 310 g / l.) The solution is left for 3 days at room temperature The precipitate is then filtered off with suction, washed with water and dried in a desiccator, giving 10.1 = 85% of theory of α-hydroxycyclopentyl-o-chlorophenyl ketone N-methylimine, mp: 58 -61 ⁰ C.

Example 4

11.2 g (0.05 mol) of α-hydroxycyclopentyl-o-chlorophenyl ketone, 50 ml of methanol and 10 ml (0.1 mol) of aqueous Methylami η solution are heated under reflux for 8 hours. After cooling, work-up is continued as in Example 3. This gives 10.6 = 89% of theory of α-hydroxycyclopentyl-o-chlorophenyl ketone N-methylimine, mp: 57-60 ° C.

Example 5

9.5 g (0.05 mol) of α-hydroxycyclopentyl phenyl ketone, 50 ml of ethanol and 7.5 ml of ammonia, 25%, are stirred for 18 hours at 55 ° C. After cooling the reaction solution is worked up as in Example 3.

This gives 8.5 = 90% of theory of a-hydroxycyclopentyl phenyl ketone-imine, m.p .: 89-91 ⁰ C.

Example 6

22,4g (0.1 mole) of a-hydroxycyclopentyl-o-chlorphenylketon, 100 ml of methanol and 20 ml (0.2 mol) of aqueous methylamine solution is stirred for 18 hours at 55 ⁰ C. Thereafter, the solution is distilled under reduced pressure in a water bath of maximum 5O ⁰ C to one-third of its volume and are then added to 300 ml of cold water. The precipitate is filtered off with suction, washed with water and poured into 120 ml of toluene. After drying over Na ₂ SO ₄ , the solution is distilled to remove all water. Thereafter, HCI gas is passed into the solution until the pH is 1-2.

The precipitated α-hydroxycyclopentyl-o-chlorophenyl ketone N-methylimine hydrochloride is filtered off with suction and washed well with acetone.

After drying, 23 g = 84% of the theory of a light yellow, microcrystalline salt of mp.: 170-175 ° C (decomposition).

Claims (1)

1. A process for the preparation of α-hydroxyketimines of the general formula 4 OH NR ₁ in the Ri is hydrogen or a lower alkyl group having 1 to 2 C atoms, R _{2 is} hydrogen or chlorine and R ₃ and R _{4 are} each a methyl group or R ₃ and R ₄ together with the C atom to which they are attached , a cyclopentyl group and their salts with inorganic acids by reacting a-hydroxy ketones of the general formula