NO128773B - - Google Patents

Description

Process for the production of therapeutically effective dibasic phenylacetic acid esters.

During the synthesis of phenylacetic acid esters

with two basic substituents, it has been shown that it is possible to obtain new compounds which are valuable for therapeutic purposes, especially compounds with spasmolytic action and compounds which have a calming effect on the central nervous system.

These new compounds include basic esters with the below-mentioned formula (1)

or water-soluble salts or quaternary ammonium compounds thereof, in which formula n is 1 or 2, R denotes a hydrogen atom, denotes a diethylamine, piperidine or morpholine group and when n = 1 also a 1, 2, 5, 6-tetra- hydropyridine group or R, and R2 can, in the case where n = 1, together form a trimethylene chain, which unites CH and N, in which case R3 denotes an ethylene group, and R means a 1, 2, 5, 6-tetrahydropyridine or piperidine - as well as for n = 1, also a pyrrolidine, morpholine, 3- or 4-methylpiperidine group, although R for n = 1 cannot mean a piperidine group, when means a diethylamine or piperidine group. The present invention concerns a method for the preparation of compounds corresponding to the formula (1), and the peculiarity of this method is that halogen compounds with the general formula where n, Rj, R2 and R3 have the same meanings as above, and hal denotes a halogen atom, preferably a chlorine atom is condensed in the presence of a hydrogen halide binding agent with a secondary amine of the formula

where R has the same meaning as above, and that the basic esters thereby obtained are optionally transferred to salts, preferably dihydrogen chlorides, or quaternary ammonium compounds, preferably diiodomethylates, the condensation being preferably carried out in an anhydrous organic solvent

agent, especially in benzene at reflux temperature.

Instead of using benzene, other aromatic coal-water substances, such as toluene or xylene, can optionally be used.

Esters corresponding to formula (1) all have a spasmolytic character, but α-phenyl-α-tertiary aminoacetates of p-diethylaminoethyl' are of particular interest because they also have a central sedative effect.

The dibasic esters corresponding to formula (1) are viscous oils that can be distilled at very low pressures and are soluble in organic solvents, e.g. alcohol, ether and benzene, but are not soluble in water. In order to be used in practice, it is in most cases advantageous to transfer them in water-soluble derivatives, especially in acidic addition salts or, in the case of the esters corresponding to formula (1), where n = 2, in biquaternary ammonium compounds at to use commonly known methods. According to the invention, dihydrogen chlorides and dihydrogen bromides can be produced in particular. The dihydrogen chlorides are mostly crystalline, white compounds that are easily soluble in water but insoluble in ether.

Some of the biquaternary ammonium compounds of the esters corresponding to formula (1) where n = 2 form drugs which have a very advantageous therapeutic index.

The halogenated compounds corresponding to formula (2) can be prepared by using known methods for the preparation of esters, e.g. starting from a functional derivative of α-phenyl-α-haloacetic acid, in particular by reacting a chloride of this acid with the relevant alcohol in an anhydrous organic environment and subsequent release of the base from the hydrochloride formed by the action of an alkali.

The following examples illustrate the invention.

Example 1:

(a) p-tetrahydro-1,2,5,6-pyridineethanol. In a 2-liter, three-ported balloon, equipped with mechanical tubing, a bromine ampoule, and a reflux condenser, 11.5 g (0.5 mol/g), metallic sodium was dissolved in 290 cm<3 > absolute alcohol. - To this solution was added 41.5 g (0.5 mol/g) tetrahydro-1, 2, 5, 6-pyridine. The resulting mixture was cooled in an ice bath. Through the bromine ampoule, 48.3 g (0.6 mol/g) of glycol chlorohydrin were poured in over the course of an hour. .... The mixture was heated for 7 hours

with reflux, cooled, the sodium chloride formed removed and washed 3 times with absolute alcohol.

The alcohol was removed from the filtrate by distillation on a water bath and the residue was rectified in vacuo.

'• 42 g (yield = 66.1%) of tetrahydropyridine ethanol was obtained which distilled

■,6ver at 80—81° under a pressure of 6 mm Hg.

Tetrahydro-1, 2, 5, 6-pyridinoethanol is a colorless oil that is soluble in water, alcohol and ether and also in most organic solvents. Its hydrochloride, which was obtained by dissolving the base in anhydrous ether and by passing a stream of gaseous dry hydrochloric acid into this etherified solution, is after re-crystallization in a mixture of methyl ethyl ketone and alcohol (5:1) in a white crystallized substance that is slightly hygroscopic and soluble in water. The substance melts at 105-107° C.

Analysis:

Cl calculated = 21.71%

Cl found = 21.64%

b) Hydrochloride of a-phenyl-a-chloroacetate of diethylamine ethyl.

To a solution of 245 g (1.29 mol/g)

a-phenyl-a-chloroacetic acid chloride, prepared as indicated by Bischoff and Walden, Annalen Liebig, 279 (1894), p. 122, in 1000 cm<3 > of anhydrous ether there was, after the solution had been cooled on an ice bath, slowly and with continuous stirring, 151 g (1.29 mol/g) of p-diethylamine ethanol was added to 800 cm<3> of anhydrous ether (addition time: 1 hour).

The hydrochloride of a-phenyl-a-chloroacetate of diethylamine ethyl immediately separated in the form of a white crystallized precipitate.

After the addition was finished, the mixture was kept for another hour in an ice bath and then allowed to stand for 24 hours at ambient temperature. The mixture was dried, washed several times with anhydrous ether and then dried in air.

A sample of the crude material, recrystallized

in isobutyl alcohol melts at 123°.

Analysis:

Cl calculated = 11.60% Cl found = 11.71% c) a-phenyl-a-chloroacetate of diethylamine ethyl.

The hydrochloride of a-phenyl- a-chloroacetate

of the crude diethylamine ethyl from which 357 g (yield = 90.6%) were obtained was dissolved in 1000 cm<3> of water. The aqueous solution was made alkaline to a pH value = 9

by means of a saturated solution of sodium carbonate and a-phenyl a-chloroacetate of diethylaminoethyl separated in the form of an oil which was extracted successively 4 times with 500 cm<3> of ether.

The combined ether extracts were dried over sodium sulfate, the ether removed and the crude diethylamine ethyl α-phenyl-α-chloroacetate (236 g) was used at once in the following reaction. d) α-phenyl-α-tetrahydro-1,2,5,6-pyridine acetate of diethylamine ethyl.

To 56.4 g (0.21 mol/g) α-phenyl-α-chloroacetate of diethylamine ethyl in 250 cm<3> anhydrous benzene was added 34.8 g (0.42 mol/g) tetrahydro- 1, 2 , 5, 6-pyridine. The mixture was heated for 8 hours under reflux, cooled, the precipitated tetrahydropyridine hydrochloride was dried and washed several times with anhydrous benzene.

The filtrate was combined with the benzene-containing wash water and the benzene removed by distillation on a water bath (the last traces under vacuum).

The oil which remained was taken up in 200 cm<3> of water, stirred for a few minutes in a decanting vial and subjected to three successive extractions with 200 cm<3> of ether each time.

The combined ether extracts were dried over sodium sulfate, the ether removed and the oil distilled under high vacuum.

45.5 g (yield = 68.9%) of α-phenyl-α-tetrahydro-1,2,5,6-pyridine acetate of diethylamine ethyl was obtained which distilled over at 167-170° under a pressure of 0.8 mm Hg in the form of a pale yellow viscous oil. e) The hydrodichloride of α-phenyl-α-tetrahydro-1, 2, 5, 6-pyridine acetate of diethylamine ethyl.

A stream of dry hydrogen chloride gas was introduced into a solution of 10 g of α-phenyl-α-tetrahydro-1,2,5,6-pyridine acetate of diethylaminoethyl in 400 cm<3> of anhydrous ether until precipitation ceased. The hydrochloride was dried, washed twice with anhydrous ether and dried in vacuo.

The hydrochloride was purified by dissolving it in as little isopropyl alcohol as possible and by reprecipitating it using a large volume of anhydrous ether.

The hydrodichloride of a-phenyl-a-tetrahydro-1, 2, 5, 6-pyridine acetate of diethylamine ethyl is a white substance which is extremely hygroscopic and whose melting point cannot be determined.

Analysis:

Cl calculated = 18.25%

Cl found 17.72%

f) The hydrodibromide, prepared in the same way, has the advantage that it is not

hygroscopic. It melts at 200°C and is soluble in water and ethyl alcohol, but insoluble in methyl ethyl ketone.

Example 2:

By proceeding as indicated in example 1, but replacing (3-diethylamineethanol with (3-tetrahydro-1, 2, 5, 6-pyridineethanol and tetrahydro-1, 2, 5, 6-pyridine with piperidine), the following was eventually obtained: a) Hydrochloride of α-phenyl-α-chloroacetate of [3-tetrahydro-1, 2, 5, 6-pyridineethyl

(yield 63.3%) an oily substance.

b) the corresponding free base,

c) α-phenyl-α-piperidine acetate of (3-tetrahydro-1, 2, 5, 6-pyridineethyl (yield 61.4%), a pale yellow viscous oil which distilled over at 180-182° under a pressure of 0, 5 mm Hg. d) The hydrodichloride of the base (c) which, recrystallized in a mixture of methyl ethyl ketone and ethanol (2:1) formed a white substance, crystallized, not hygroscopic and very soluble in water and melting at 225-226°.

Analysis:

Cl calculated = 17.70%

Cl found = 17.70%

By proceeding as indicated in example 1, the following have been prepared: (A) Hydrochlorides of α-phenyl-α-chloro-acetates of, (B) Compounds corresponding to the formula and their hydrochlorides.

Example 3: a) The hydrochloride of a-phenyl-a-chloroacetate of diethylaminetoxyethyl..

12.9 g (0, 08 mol/g) diethylamine ethoxyethanol in 100 cm<3> anhydrous ether (addition time: 30 minutes).

Hydrochloride of the α-phenyl-α-chloroacetate of the crude diethylamine oxyethyl was dissolved in paste form.

After completion of the addition, the mixture was kept for a further 2 hours in an ice bath with stirring, and then allowed to stand for 24 hours at ambient temperature. The ether was decanted. b) (α-phenyl-α-chloroacetate of diethylamine oxyethyl.

Hydrochloride of the a-phenyl-a-chloroacetate of the crude diethylamine oxyethyl was dissolved in as little water as possible. The aqueous solution was made alkaline to a pH value = 9 with a saturated solution of sodium carbonate and α-phenyl-α-chloroacetate of diethylaminoethoxyethyl separated in the form of an oil which was extracted four times with 100 cm<3> of ether.

The combined ether extracts were dried over sodium sulfate, the ether removed, and the crude diethylaminoethoxyethyl α-phenyl-α-chloroacetate (22.1 g, yield 88%) used at once in the following reaction. c) α-phenyl-α-tetrahydro-1,2,5,6-pyridine acetate of diethylaminoethoxyethyl.

To 22.1 g (0.071 mol/g) α-phenyl-α-chloroacetate of diethylamine oxyethyl dissolved in 150 cm<3> of anhydrous benzene was added 11.8 g (0.142 mol/g) tetrahydro-1, 2, 5, 6-pyridine. The mixture was heated for 8 hours under reflux, cooled, the precipitated tetrahydro-1,2,5,6-pyridine hydrochloride was removed and washed several times with anhydrous benzene.

The filtrate was combined with the benzene-containing wash water and the benzene removed by distillation on a water bath (the last traces under vacuum).

The remaining oil was taken up in 50 cm<3> of water, after stirring for a few minutes in a decanting ampoule, three successive extractions were carried out, each time with 120 cm<3> of ether.

The combined ether extracts were dried over sodium sulfate, the ether removed and the oil rectified twice under high vacuum.

10.7 g (yield 42%) of α-phenyl-α-tetrahydro-1, 2, 5, 6-pyridine acetate of diethylamine oxyethyl was finally obtained, which distilled over at 189-191° at a pressure of 0.3 mm Hg in form of a pale yellow viscous oil. d) The hydrodichloride of α-phenyl-α-tetrahydro-1, 2, 5, 6-pyridine acetate of diethylamine oxyethyl.

To a solution of 5.4 g of α-phenyl-α-tetrahydro-1, 2, 5, 6-pyridine acetate of diethylamine oxyethyl in 100 cm<3> of anhydrous ether, a solution of hydrochloric acid in anhydrous ether was added dropwise until the precipitation stopped. The hydrochloride was dried, washed several times with anhydrous ether and dried in vacuo.

The hydrodichloride of a-phenyl-a-tetrahydro-1, 2, 5, 6-pyridine acetate of diethylamine oxyethyl, recrystallized in anhydrous acetone has the form of a white crystallized substance, soluble in water and in alcohol, but insoluble in ethyl acetate and methyl ethyl ketone and hygroscopic. It melts at 161°.

Analysis:

Cl calculated = 16.39%

Cl found =16.04%

e) Diiodomethylate of α-phenyl-α-tetrahydro-1, 2, 5, 6-pyridine acetate of diethylamine oxyethyl.

To a solution of 3.6 g (0.01 mol/g)

α-phenyl-α-tetrahydro-1, 2, 5, 6-pyridine acetate of diethylamine oxyethyl in 15 cm<3> of anhydrous acetone was added 2.9 g (0.02 mol/g) of methyl iodide. The mixture was allowed to stand for three to three days at ambient temperature, the precipitated iodomethylate dried, washed with anhydrous acetone and dried in vacuo.

5.5 g (yield 84.6%) of diiodomethylate of α-phenyl-α-tetrahydro-1, 2, 5, 6-pyridine acetate of diethylamine oxyethyl was finally obtained, which recrystallized in absolute alcohol has the form of a crystallized white compound, soluble in water and not hygroscopic. It melts at 167°.

Analysis:

In calculated = 39.44

I found = 39.54

By proceeding as in example 3

it was likewise produced:

(A) Hydrochlorides of a-phenyl- a-chloro-acetate of

Piperidine oxyethanol can be prepared as follows: A mixture of 50 g (0.3 mol/g) (chloro-2'-ethoxy)-2-ethyl acetate prepared as indicated by Blicke and Biel, Journal of the American Chemical Society, 76

(1954), p. 3164 76.5 g (0.9 mol/g) of piperidine and 75 cm<3> of absolute alcohol were heated in a sealed tube to 120-125° for 18 hours. The alcohol was removed on a water bath (the last traces in vacuum). The residue was taken up in 30 cm<3> of water and then made alkaline with 40 cm<3> of 40% caustic soda. After stirring for a few minutes in a decanting ampoule, the separated oil was extracted 4 times with 100 cm<3> of ether.

The combined ether extracts were dried over sodium sulfate, the ether removed and the remaining oil rectified in vacuo.

39.5 g (yield 76%) of piperidine ethoxyethanol were finally obtained in the form of a colorless liquid which distilled over at 105-106° at a pressure of 3 mm Hg.

The hydrochloride of this compound, recrystallized from acetone, takes the form of a white, crystallized compound, which is slightly hygroscopic and water-soluble. It melts at 120°.

Analysis:

Cl calculated = 16.94%

Cl found = 16.94%

Morpholine oxyethanol prepared in an analogous manner with a yield of 69.7% is a colorless liquid which distills above at 106-108° at 3 mm Hg.

Its hydrochloride, recrystallized from isopropyl alcohol takes the form of a crystallized white compound which is soluble in water. It melts at 157°.

Analysis:

Cl calculated = 16.78%

Cl found = 16.65%

(B) Compounds corresponding to the formula:

CsHo

IN

R-CH-COO-CH2-CH2-0-CH2-CH2-R' their dihydrochlorides and their diiodomethylates.

Claims (2)

1. Process for the production of therapeutically effective dibasic phenylacetic acid esters with the general formula or water-soluble salts or quaternary ammonium compounds thereof, in which formula n is 1 or 2, R, denotes a hydrogen atom, denotes a di ethylamine, piperidine or morpholine group and when n = 1 also a 1, 2, 5, 6-tetrahydropyridine group or R, and R2 can in that case, where n = 1, together form a trimethylene chain, which unites CH and N, in which case R3 denotes an ethylene group, and R means a 1, 2, 5, 6-tetrahydropyridine- or piperidine — and for n = 1, also a pyrrolidine-, morpholine-, 3- or 4-methylpiperidine- group, although R for n = 1 cannot mean a piperidine group when mean a diethylamine or piperidine group, characterized in that halogen compounds of the general formula where n, R1, R2 and R3 have the same meanings as above, and hal denotes a halogen atom, preferably a chlorine atom is condensed in the presence of a hydrogen halide binding agent with a secondary amine of the formula where R has the same meaning as above, and that the basic esters thereby obtained are optionally transferred to salts, preferably dihydrogen chlorides, or quaternary ammonium compounds, preferably diiodomethylates. 2. Method as set forth in claim 1, characterized in that the condensation is carried out in an anhydrous organic solvent, preferably in benzene at re-cooling temperature.