NO128798B - - Google Patents

Description

Process for the production of therapeutically active basic esters.

It is known that among the phenyl acetates

of (3-diethylamino-ethyl) with an additional substituent on the carbon atom which

compounds bearing the phenyl group are found

with spasmolytic effect.

It has now been shown that α-phenyl-α-piperidine-acetates of (3'-Alkoxyethyl) have spasmolytic, local anesthetic and antitussive

properties and that, due to their non-toxic nature, they are of great importance to

therapeutic use, particularly in the form of water-soluble salts.

The present invention relates to a

method for producing these

basic esters and this method consists in ct-phenyl-α-haloacetates of β'- alkoxyethyl being condensed with piperidine in

presence of a fixative for it

formed hydrohalic acid, preferably

in an anhydrous and inert organic environment.

In particular, a suitable can be used

excess of piperidine as fixing agent for hydrochloric acid. The organic

water-free and inert environment can consist of a

aromatic carbon hydrogen, especially of benzene.

α-Phenyl-α-haloacetates, especially α-phenyl α-chloroacetates, of (5'-Alkoxyethyl is

new. They can be produced using any known esterification process,

in particular by reacting α-phenyl-α-halogenoacetic acid chlorides with β-alkoxyethanols.

α-Phenyl-α-piperidine acetates of |3'-Alkoxyethyl having the general formula

where R is an alkyl group, are generally colorless liquids which distil in vacuo, are soluble in alcohol, ether and other common organic solvents, but insoluble in water. Their hydrochlorides, such as can be obtained by dissolving the bases in anhydrous ether and by passing a stream of dry hydrogen chloride gas into the ether solution, are crystallized and white substances, some of which are very hygroscopic. They are soluble in water. In return, the hydrobromides are not hygroscopic and very soluble in water and ethyl alcohol, so that they are more convenient to use.

Particularly important compounds in this class are the hydrochloride and hydrobromide of α-phenyl-α-piperidine acetate of |3'-n-butoxyethyl. They can be equated with papaverine in terms of their musculotropic spasmolytic effect, and they have a 5 times greater local anesthetic effect than procaine on the cornea of rabbits. They also have a 2 to 3 times greater antitussive effect than codeine.

Finally, their DL 50 amounts to 155 mg/kg (the hydrochloride) and 220 mg/kg (the hydrobromide) intravenously in white mice (Kaérber and Behrens method). These ver-

is thus lower than for procaine and codeine.

α-Phenyl-α-chloroacetates of fS'-Alkoxy-

ethyl are generally colorless liquids that do not distil over even at high vacuum, are soluble in alcohol, ether and other common organic solvents

clay, but not soluble in water.

The following example illustrates the invention:

Example:

a) α-phenyl-α-chloroacetate of |3'-n-butoxy-

ethyl.

In a 250 cm<3->balloon with three openings

ger, equipped with a mechanical stirrer, a bromine ampoule and a reflux condenser, a solution of 38 g (0.2 mol/g) α-phenyl-α-chloroacetic acid chloride was introduced dropwise and with mechanical stirring into 30 cm<3> ( 3-n-butoxyethanol (addition time 20 minutes-

ter). The mixture was heated under

winding of hydrochloric acid. The reaction was terminated by heating for 2 hours at

a boiling water bath.

After cooling, 250 cm<3> was added

water, and after vigorous stirring the separated oil was subjected to three successive extractions with 150 cm<3> of ether. They co-

pale ether extracts were dried over sodium

sulfate and the ether removed (the last traces on

a water bath in a vacuum).

In this way, 54 g (yield 100%) of α-phenyl-α-chloroacetate of β-3'-n-butoxyethyl was obtained, which is used in the crude state in the following reaction. b) α-phenyl-α-piperidine acetate of p'-n-but-oxy-ethyl.

A mixture of 27 g (0.1 mol/g) α-phenyl-α-chloroacetate of p'-n-butoxyethyl and 17

g (0.2 mol/g) of piperidine in 150 cm<3> of anhydrous benzene was heated for 8 hours under reflux.

The reaction mixture was cooled, the piperidine hydrochloride removed, and then washed 3 times with benzene. The benzene was removed from the filtrate (mixed with the benzene-containing wash water) by distillation on a water bath, the oily residue was slurried with 100 cm<1> of water and then subjected to three successive extractions with 100 cm<3> of ether. The ether extracts were combined and washed successively 2 times with 70 cc

water, dried over sodium sulfate, the ether removed

net and the remainder rectified in vacuum.

22.1 g were obtained (yield 69.2

%) a-phenyl-a-piperidine acetate of p-n-butoxyethyl in the form of a colorless oil which de-

settles over at 143—144° at 0.2 mm.

The substance is soluble in alcohol and ether, but insoluble in water.

c) The hydrochloride of the base (b).

The base was dissolved in anhydrous ether, and i

ether solution, a stream of dry hydrogen chloride gas was introduced. After drying in vacuum on phosphoric anhydride, the

separated hydrochloride excreted. It is an amorphous,

very hygroscopic and water-soluble substance.

d) Hydrobromide of the base (b).

Prepared in a similar manner and recrystallized from methyl isopropyl ketone, the hydrobromide melted at 99°. The fabric is very high-

soluble in water and alcohol.

In a similar way, it can be produced:

(e) p'-methoxyethyl α-phenyl-α-piperidine acetate in a yield of 74%. This substance boils at 131—132° at 0.4—0.5 mm,

and its hydrochloride is hygroscopic; its hydrobromide melts at 108° and is very soluble in water and alcohol.

(f) α-phenyl-α-piperidine acetate of (3'-ethoc-

syethyl with a yield of 67.8%. This substance boils at 140-141° at 0.5 mm, and its hydrochloride melts at 105° after recrystallization in ethyl acetate. The hydrobromide melts at 137-138° and is very soluble

soluble in water and in alcohol.

(g) p'-n-hexyloxyethyl α-phenyl-α-piperidine acetate in a yield of 70.6%. This substance boils at 161—162° at 0.7—0.8 mm,

and its hydrochloride is hygroscopic. Its hydrobromide melts at 90—91° and is me-

get soluble in water and alcohol.

1. Process for the production of therapeutically active basic esters having the general formula

Claims (3)

where R is an alkyl group, characterized in that an a-phenyl-a-haloacetate of p'- alkoxyethyl is condensed with piperidine, in the presence of a fixing agent for the hydrohalic acid that is formed, preferably in an anhydrous and inert organic environment. 2. Method as set forth in claim 1, characterized in that the obtained α-phenyl-α-piperidine acetates of β-3'-alkoxyethyl are converted in a known manner into salts which are soluble in water, in particular into hydrochlorides or hydrobromides. 3. Process as set forth in claim 1, characterized in that an acidic α-phenyl-α-haloacetate of β-3'-n-butoxyethyl is reacted with piperidine.