DD204081A1 - PROCESS FOR THE PREPARATION OF ALPHA-HYDROXYKETIMINES AND THEIR SALTS - Google Patents

Abstract

Alpha-hydroxyketimines of the general formula I can be prepared industrially easily and in good yields by reacting alpha-hydroxy ketones of the general formula II with aqueous solutions of amines of the general formula III in the presence of a solvent and, if desired, the compounds of the general formula I obtained into their acid addition salts.

Description

234435 4

Title of the invention

Process for the preparation of oC-hydroxyketimines and their salts

Field of application of the invention

The invention relates to a process for the preparation of

the general Pormel '

in which IL is hydrogen or a lower alkyl group sit 1 to 4 · C atoms, E hydrogen or halogen and HL · and xL alkyl groups having 1 to 3 carbon atoms, which may optionally be closed together to form a 3- to 7-membered Hing , and their salts with inorganic acids,

Such hydroxy and hydroxy ketimines are valuable intermediates in the drug industry.

By thermal rearrangement, they can be converted into ~ <-aminoketones, which exert a strong effect on the central nervous system and thus constitute highly effective pharmaceuticals.

Characteristic of the known technical solutions

Ss is known to be α-dihydroxy ketone imine by reaction of 4-bromoketones,. ^ - Hydrozyketonen. or to prepare their ketals with amines according to the following formula scheme. j

3

C-C-

• 4 OH

CH ₃ OHa

E.

OCH

s "

C-C

I! OH 0

In these! Formulas have meaning,

to H ₂ , the above

So you can <p <-Bromketone at temperatures between -60 ⁰ G and -30 ⁰ C with liquid ammonia or liquefied aliphatic amines to ^ -Hydrosyketiininen implement OÄ-PS 1202834, DE-AS 129376I ₅ J.Amer, Chea »Soc. <£ (1973)? 1978) # The temperatures required for the reaction in the desired sense can be achieved under laboratory conditions by cooling with dry ice, but they are difficult to realize on an industrial scale.

That is a major disadvantage of this procedure.

If, however, the reaction is allowed to proceed at elevated temperatures or in solvents, the undesirable Y- aminoketones or mixtures of the two isomeric compounds which are practically not separable are obtained instead of the desired X-hydroxyketimines (J. Amer. Chem. Soc. 2% (1973), 1978):

HH,

Lösangsm

 elevated door

It has been attempted to circumvent the low temperatures by first passing the o-3-meth-ketones with equivalent amounts of methanolic sodium methacrylate solution into a ketal of the corresponding o-hydrosyl ketone, and then adding this to a 1-hydroxyethyl ketone ums et zt ·

For example, 2-methoxy-2-phenyl-1-o2a.spiro - / "" 2,4_7-beptane was reacted with toluidine to give 1- (^ -p-toluenediynobenzyl) -cyclopentanol. For this it was necessary to "heat up to · and the" 30 minutes at 110 ⁰ C during the 'Eesktion · formed distill methanol simultaneously under reduced pressure (J "Org * JJQ (1,965), 2962)" This process however, is limited to heavy amines such as toluidine.

_ Zl - - ¹ ™ "^

In order to be able to react the ketals with highly volatile amines, for example methylamine, autoclaving was carried out under pressure. However, this procedure led to the isomeric aminoketones (DE-AS 1293761 see Example 2 last section) and is therefore useless »

It is also known that c <-hydroxyketones in -X-Hy drosyk et imne to convert, by reacting with amines either at tree temperature in a closed vessel for several days or at temperatures around 100 ⁰ C for several hours to several days in an autoclave » An addition of potash or caustic soda should thereby shorten the reaction time (DB-AS 1293761, J. Amer. Chem. Soc., 8J> (1963), 1464, ibid. 88 (1966), 2769, J. Org. Chem O (1965), 2967, ibid. J (1966), 2593 and 2601, ibid. Ji (1972), 2091, J. Amer. Chem. Soc., 9 (1973), 1978) *

In these methods, it is necessary to work with a large excess of amine, which after. Termination of the reaction must be caught. In terms of environmental protection, such a procedure is associated with additional technical effort.

The hitherto known technical solutions for the preparation of ^ -Hydrozyketiminen thus require the generation of low temperatures or pressure reactions, are associated with long reaction times and with high expenditure'absorp tion and recovery of the amines, or lead to the simultaneous formation of the undesired isomeric; X-aminoketones. Moreover, in all known technical solutions, the cx'-Hjdrosyk et imine unclean * Ss lacks a simple method for obtaining o ( ketimines »

Object of the invention

The invention makes it possible to produce <x-hydroxyketimines of general formula I in a technically easy and reaction-free reaction time without having to produce low temperatures. Also, the amount of amines used is kept within such limits that recovery is not required. "

The c <-K; ydro3 ^ ketimines are obtained in high yields and of excellent quality, so that they do not have to be purified before further processing. "

Explanation of the essence of the invention

The present invention has as its object vC-Hydrosyketimine of the general formula I, in which the radicals IL to IL have the abovementioned meaning, in good yields and high purity, in reasonable reaction times, while avoiding pressure reactions, without generating low temperatures establish "

According to the present invention, this is achieved by reacting c <-hydroxyketones of the general formula

OH 0

in which the radicals R ₂ to R ₁ . have the abovementioned meaning in a solvent with an aqueous solution of an amine of the general formula

R ₁ -BH,

III

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

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

The amount of solvent is not limited. For convenience, you can use 5 to 10 times the amount of alcohol. «

The molar ratio of the reactants is also variable, but at least 1 to 3 moles of the amine in question should be used per mole of hydrogen per mole.

The reaction times depend 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 titrimetrically * This is a particular advantage of the process according to the invention *

The work-up of the reaction solution can take place in various ways,

So you can pour the solution in 4- to δ-fold amount of water (based on the amount of solvent used) and the thereby precipitated cc-By drosyketimin the general formula I aspirate *. In order to reduce the amounts of solvent, it is also possible to substantially distill off the alcohol used as solvent after completion of the reaction and the residue in 4- to 6-fold

234435

Amount of water (based on the volume of the residue) to give »As above, one wins the H ^ dros ^ ketimin of the general formula I by suction *

The yields are consistently above 85% and the ketimines fall in such high purity that _it's as long as it is desired _s? The preparation of the salts from the obtained compounds of the general formula I can be carried out in a manner known per se in two ways, by reacting either the ortho -diethoxy ketimine in 4 to 6 times the amount of an organic solvent , z · B · toluene or acetone is dissolved and hydrogen chloride is introduced into the acidic reaction or treated with an appropriate amount of isopropanolic hydrochloric acid * The hydrochloride precipitates and. can be isolated by suction · In place of hydrogen chloride or hydrochloric acid, other acids can be used in the same way for salt formation _β

The use of aqueous solutions of the amine of general formula III is surprising and unforeseeable for a person skilled in the art because of the reaction of the amine with the equation

+ H ₂ O

Water forms as a second reaction product and thus aqueous solutions should shift the balance to the left *

η r

234435

The inventive method has over the known technical solutions following Torteile5

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

- Ss is not necessary to generate with respect to the low boiling points of the pure amines for reaction temperatures from -60 to -30 ⁰ G, but it may in be worked room temperature or easily realizable temperatures between 20 and 70 ⁰ C '

-] The autoclave is not needed for the reaction · It can be used in simple laboratory flasks, hanging vessels or boilers «.

- The reaction can be easily determined by determining the amount of amine consumed. Titration be controlled and tracked, the amines need only be used in slight excess *

- The cX'-H ^ drosyketimine so clean that they can be converted into their salts without gedseehenreinigung and, if appropriate, suitable for further reactions in this form

Exemplary embodiments Example 1

16.4 s (0.1 EoI) o ^ -H ^ drosyisoprop ^ i-phenyl ketone is dissolved in 100 ml of methanol and 15 ml of concentrated ammonia (25%) to "The solution is stirred for 18 hours at SO ⁰ C and then poured into 540 ml of water. In this case, the x-hydrosiliconisoprop-1-phen; ketone-imine, Ss is filtered off with suction, washed with water and dried in air, giving 14.4 g = 88 % of theory, Ipi 82-84 ⁰ C,

Example 2

S 12 g (0.05 mole) of (X-hydroxysopropyl-phenylfetone in 50 ml of methanol are added with 12.5 μl (0.11 mole) of an aqueous solution of ethylaroin (400 g / liter) and allowed to stand at room temperature for 5 days The solution in 27% sodium water * The precipitating oil solidifies after some time, it is filtered off with suction, washed with water and dried in an Exslfrfrator ·

This gives 17.8 g of 93 % of theory cetfphen-1-ketone-H-ethylimine, mp: 36 - 37.5 ⁰ G.

Example 3

11 ml of (0.05 mol) of -H ^ dro ^ cyclopent-1-o-ketone are dissolved in 1 ml of methanol and admixed with 10 ml (0.1 mol) of aqueous methylamine solution (content 310 g / l). The solution is left to stand at tree temperature for 3 days and then poured into 270 ml of water. The precipitate is filtered off with suction, washed with water and dried in an issifier.

This gives 10.1 g = 85% of theory of ^ - ^ pent-lo chlorphen ^ lketon-lä-meth ^ limin, Pp s 58.- 61 ⁰ C ·

Example 4

11.2 g (0.05 mol) of X-ketone, 50 ml of methanol and 10 ml (0.1 mol) of aqueous solution of methamine are heated under reflux for 8 hours. the cooling is continued as in Example 3 worked up *

Man. Receives 10.6 g = 3 $% of theory

Pp ι 57 - 60 ⁰ C *

Example 5

9 »S 5 (0.05 mol) ^ ^ -Hydrosyc clopent ^ l-phenyl ketone, 50 ml of ethanol and 7.5 ml of 25% strength ammonia are stirred for 18 hours at 55 ⁰ C · laughing cooling of Beaktionslösung is as in Example 3 worked ·

This gives 8.5 g = 90 % of theory of c-pentyl-phsn-1-acetone-imine, Pp, 89-91

Example 6

22.4 · g (0.1 mole) cK-H ^ drosjcyclopent 100 ml of methanol and 20 ml (0.2 mol) of aqueous Methjlamin-.lösung 18 hours at 55 ⁰ C stirred, the solution is then distilled under reduced pressure in a water bath of a maximum of 50 ⁰ G to one third of their Yolusens and then to 300. ml of cold water, the precipitate is filtered off with suction, washed with water and in 120 ml of toluene, if ach drying over 2Ta ₂ SO ₂ , is The solution is distilled to remove all water, then HCl gas is bubbled into the solution until the pH is 1-2.

The failed ^

U-Aimethyl-h ^ drochicrid is filtered off with suction and washed thoroughly with acetone *

After drying, 23 g * 84 % of the theory of a pale yellow, microcrystalline salt -ppi 170 - 175 ⁰ C (decomposition),

λ η

Claims (6)

234435 4 ent to cmc he 1. A process for the preparation of c ^ -hydroxyketimines of the general formula in which 3L is hydrogen or a lower alkyl group having 1 to 4 C atoms, Hp is hydrogen or halogen and E 1 and E ₂ , are each alkyl groups having 1 to 3 C atoms, which may also be combined with one another to form a to 7-membered Sii ^ei 3-Hing may be closed, and of their salts with inorganic acids by reaction of ^ -. HydiOsyketonen of the general formula II in the Hp to H ^ have the abovementioned meaning, with amines of the general formula in which H 1 has the abovementioned meaning / at temperatures between high temperature and elevated temperature, characterized in that the hydroxyketones of the general formula II are reacted with aqueous solutions of the amines of the general formula III in the presence of a solvent and desirably 2. The method according to item 1, characterized in that the solvent used is lower alcohols · 3 »method according to the points 1 to 2, characterized in that per mole of cX-Hjdrosqyketon the general formula II 1 to 3 moles of Arnin of the general formula III are used. 3. Γ CL Ti ^- ._ * 'ph , ο ύ Cj if the compounds of general formula I obtained are converted into their acid addition salts 4. The method according to the items 1 to 3j characterized in that the reaction at 'temperatures between hem temperature and 70 ⁰ C is performed * 5. Process according to items 1 to 4, characterized in that the resulting mixture of heatses, if appropriate after evaporation to a part of the original volume, is added to water and the precipitated e1 -H2-dihydroxetane of the general formula I is isolated, 6 »process according to the points 1 to 5} characterized in that one converts the resulting ^ -H ^ droxyk et iniine of the general formula I in their salts, preferably in their hydrochlorides,