This application is a continuation-in-part of my earlier filed United States application Serial Number 127,868, filed July 31, 1961, for Process for the Preparation of Aminoketones, now abandoned.
This invention relates to novel aminoketones, to acid-addition salts thereof, and to methods for producing the same. More particularly, the invention relates to α-aminoketones which in free base form have the formula R-CO-CR1R2-NHR3 wherein R, R1, and R3 are selected from among lower alkyl groups containing 1 to 5 carbon atoms inclusive, lower aryl groups such as phenyl and substituted phenyl moieties, and groups wherein any one of R, R1, and R2 may be combined to form an alkylene bridge of from 4 to 5 carbon atoms inclusive.
The free bases of the invention form acid addition salts by reaction with any number of acids. Non-toxic, pharmaceutically acceptable acid addition salts are formed with acids such as a hydrochloric, hydrobromic, hydriodic, sulfuric, phosphoric, acetic, citric, tartaric, and p-toluenesulfonic acids. These acid addition salts are converted to the free bases by treatment with a base such as sodium hydroxide or sodium carbonate.
Generally speaking, α-aminoketones are sparsely known in the prior art. This is because of the difficulties which are encountered in attempting to prepare such compounds. An object of this invention is to provide novel α-aminoketones. Another object of this invention is to provide a method for producing α-aminoketones from α-hydroxyketones by a rearrangement of the carbon skeleton of the hydroxyketone. A further object of this invention is to provide a method for rearranging more available α-aminoketones to get different more difficultly available α-aminoketones.
These and other objects which will appear hereinafter are realized by heating compounds of the general formula R1-CO-CRR2Z either alone or in the presence of at least one equivalent of an amine of the formula R3-NH2 wherein R, R1, R2, and R3 are as defined earlier and wherein Z represents -OH or -NHR3. When Z is -OH, at least one equivalent of the amine, R3-NH2, should be used.
In carrying out the process of this invention with a compound of the formula R1-CO-CRR2-NHR3 where R, R1, R2, and R3 are as defined earlier, I have found that the rearrangement proceeds between the temperatures of 180°C and 250°C. Preferably, I use a temperature of between 210°C and 230°C. The starting material is heated in a sealed vessel of some type, usually in a pressure bomb or in a sealed glass tube, for between 10 and 20 hours. Preferably, the reaction time is limited to 12±2 hours. While the α-aminoketone pictured above can be rearranged when it is heated alone, I have also found that an amine of the formula R3-NH2 (the same amine that is present in the starting α-aminoketone) can be used as a solvent for this pressure reaction. Preferably, the α-aminoketone is heated alone.
In carrying out the novel rearrangement of this invention by heating a compound of the formula R1-CO-CRR2-OH with an amine of the formula R3-NH2 wherein R, R1, R2, and R3 are as defined earlier, I have found that, although equivalent amounts of the α-hydroxyketone and the amine will give the desired α-aminoketone, a 2 to 3-fold excess of amine is to be preferred. At least one equivalent of the amine should be used. The heating is carried out in a sealed vessel for between 10 and 20 hours (preferably 12±2 hours) at a temperature of between 180 and 250°C (preferably 210°C to 230°C).
If desired, the intermediate α-hydroxyimine from the above reaction can be isolated. It has the formula R1-C(=NR3)-CRR2-OH wherein R, R1, R2, and R3 are as defined earlier. The α-hydroxyimines can then be rearranged to the desired α-aminoketones by heating in a solvent, preferably Decalin, at about 180°C to 250°C (preferably 185-200°C). It is also possible to prepare the above α-hydroxyimines by reacting an amine of formula R3-NH2 with a bromoketone of the formula R1-CO-CRR2-Br wherein R, R1, R2, and R3 are as defined above. As mentioned earlier, the processes of this invention involve a rearrangement of the carbon skeleton of the starting material. In fact, a skeletal-rearrangement always takes place when the above-described processes are carried out. This rearrangement can manifest itself in a simple alkyl or aryl migration or it can result in either ring expansion or ring contraction. In fact, if any two of R, R1, and R2 are combined to form a ring in the starting material, the final product will contain a ring of a different size. The following examples will show the various rearrangements which can take place:
- Alkyl-aryl migration:
- Aryl-alkyl migration:
- Ring contraction:
- Ring expansion:
- Ring expansion:
Of particular importance to this invention because of their cataleptoid activity are the compounds of the formula:
wherein X is selected from among hydrogen, halogen, hydroxy, methyl and methoxy and Y represents a lower alkyl group containing 1 to 5 carbon atoms inclusive. Those compounds wherein Y is methyl or ethyl are exceptionally good and α-methylamino-α-phenylcyclohexanone and α-ethylamino-α-phenylcyclohexanone are particularly good cataleptoid agents.
Example 15:
Preparation of 2-methylamino-2-(o-chlorophenyl)-cyclohexanone (Ketamine)
1-hydroxycyclopentyl-(o-chlorophenyl)-ketone N-methylimine (2.0 g) is dissolved in 15 ml of Decalin and refluxed for two and one-half hours. After evaporation of the Decalin under reduced pressure, the residue is extracted with dilute hydrochloric acid, the solution treated with decolorizing charcoal, and the resulting acidic solution is made basic. The liberated product, 2-methylamino- 2-(o-chlorophenyl)-cyclohexanone, after crystallization from pentane-ether, has mp 92-93°C. The hydrochloride of this compound has mp 262-263°C.
Preparation of 1-hydroxycyclopentyl-(o-chlorophenyl)-ketone N-methylimine (used above)
To the Grignard reagent prepared from 119.0 g of cyclopentylbromide and 19.4 g of magnesium is added 55.2 g. of o-chlorobenzonitrile. The reaction mixture is stirred for three days and thereafter hydrolyzed in the usual manner. From the hydrolysis there is obtained o-chlorophenyl- cyclopentylketone, bp 96-97°C/0.3 mmHg, nD25 1.5452.
To 21.0 g of the ketone is added 10.0 g of bromine in 80 ml of carbon tetrachloride. 1-bromocyclopentyl-(o-chlorophenyl)-ketone, bp 111-114°C/0.1 mmHg, is isolated in the usual manner. Since it is unstable, it must be used immediately.
The bromoketone (29.0 g) is dissolved in 50 ml of liquid methylamine. After one hour, the excess liquid methylamine is allowed to evaporate. The organic residue is dissolved in pentane, and upon evaporation of the solvent, 1-hydroxycyclopentyl-(o-chlorophenyl)-ketone N-methylimine, mp 62°C, is isolated.