SE204635C1 - - Google Patents

Description

Inventor: J 11 Biel Priority requested before September 29, 1959 (USA) The present invention relates to the formation of new chemical compounds and more particularly to a new process for producing chemical compounds having antispasmodic and central nervous system effects.

It has been found according to the present invention that an N-lower alkyl or N-aralkyl-1-3 halopiperidine can. is reacted with a dicyclic glycolic acid under non-basic conditions to give a dicyclic N-lower alkyl or aralkyl-2-pyrrolidylmethyl glycolate. This reaction map is represented by the following formulas: OOH / 111 \ N / —CH 2 -O-C — C \ R, pyrrolidyl ester in which X represents a reactive halogen atom, especially chlorine, bromine or iodine, R is a lower alkyl group or a phenyl group. lower alkyl group, which by alkyl is meant an alkyl group having 1-4 carbon atoms and R 1 and R 2 are phenyl-cyclopentyl, -cyclohexyl or 2-thienyl groups.

It is surprising that a ring contraction takes place with an acidic reagent, such as the substituted glycolic acids, since previous end-contraction contraction with basic reagents is known. A ring contraction with N-ethyl-3-chloropiperidine and amines is thus described by Reitsema.— i J. Am. Chem. Soc. 71, 2041 (1949), and with other basic reagents ay Paul and co-workers, Bull. Soc. Chim.736. The ring contraction with an acidic reagent further contradicts the earlier view, according to which N-ethyl172-hydroxymethylpyrrolidine undergoes a ring expansion during treatment with thienyl chloride and gives N-ethyl1,3-chloropiperidine, as shown by Fuson and co-workers in J. Am. Chem. SO. 70 ,. 2760.1 (1948); MI with acetic anhydride for formation. of N-methyl-4-acetimipiperidine, as described by Paul '; oh co-workers As representative N-lower alkyl-ocluaralkyl, - 3-halopiperipines, which may be glycane-, in the process of the film-related invention, may be named N-methyl-14- 14piperiperidine, N-propyl-3-bromopiperidine, N-butyl-3-chloropiperidine, benzyl-3-bromopiperidine and N-phthethyl-3-chloropiperidine.

Examples of dicyclic glycolates which can be used according to the invention are benzyl acid, phenylcyclohexylglycolic acid, phenylcyclopentylglycolic acid, phenyl-2-thienylglycolic acid, dicyclohexylglycolic acid, cli-cyclopentylglycolic glycolic acid and 2-thienocyclic acid.

The reaction is effected by intimately mixing the reagents in a suitable, non-basic, inert, liquid reaction medium 6, such as dry isopropanol and heating the mixture to elevated temperature, for example under reflux.

OOH `1S2 Dupl. at 12 p: 1/01 2204 636 Care must generally be taken to avoid excessively high temperatures, for example above about 100 ° C, because too much overheating causes rearrangement of the pyrrolidylmethyl compound to the 3-piperidyl ester. The tempera, turn, at which derma, rearrangement takes place, vmierar for the free base in question. With caution and the use of the lowest possible reaction temperature, there is no responsibility to carry out the reaction. In order for this to be able to be carried out by boiling under reflux, one must live. obviously use a suitable solvent with a sufficiently low boiling point for reaction or reflux without subsequent rearrangement to a noticeable extent.

When the reaction is complete, the reaction mixture is evaporated to dryness in vacuo, added to water, acidified and extracted with ether. After neutralization, the aqueous solution can be extracted with ether, after which the ether extracts are dried and the ether a, flushed by evaporation, leaving the dicyldic N-lower alkyl or aralkyl-2-pyrrolidylmethyl glycolate. The free base is not isolated by distillation because the required distillation temperature causes rearrangement of the pyrrolidyl ring to the piperidine group.

Acid addition salts of the tertiary bases are readily prepared by contacting the trim, ba, then with a suitable acid in the presence of a solvent such as acetone, benzene, ethane, nol, isopropanol or ether. Soin example pa. unchangeable acids can be named hydrochloric acid, sulfuric acid, citric acid, tartaric acid, succinic acid and benzoic acid.

Onium salts are easily formed by the free bawl). brought into contact with a lower alkylating agent in the presence of a suitable solvent such as anhydrous ether. The desired salt is formed rapidly and is generally precipitated from the solution.

Such lower alkylating agents such as methyl bromide, methyl chloride, methyl iodide, corresponding ethyl halides and dimethyl sulphates and diethyl sulphate are representative examples of reagents which can be used to form the onium salts.

In addition to a diecyclic N-lower alkyl or aralkyl-2-pyrrolide, ylmethyl glycolate, larger amounts of a dicyclic N-lower alkyl or aralkyl-3-piperidine glycolate of the formula R 1 is piperidyl ester in which R 1, R 2 and R 2 have the meaning given above. Thus, when reacting N-ethyl-3-chloropiperidine with phenylcyclopentylglycolic acid, about 50-80% by weight of N-ethyl-2-pyrrolidylmethylphenylcyclopentylglycolate and about 20-50% by weight of N-ethyl-3-piperidylphenylphlopylurphyrolylphyrolate 75% by weight and the piperidyl compound 25-35% by weight of the product. The melting point of such mixtures is fairly constant in the range 185-193 ° C and can not be increased by recrystallization.

When N-ethyl-3-chloropiperidine is reacted with benzylic acid, N-ethyl-2-pyrrolidylmethyl benzylate containing about 55% by weight of N-ethyl-3-piperidylbenzylate is formed in the same manner.

It is generally superfluous to divide the products into the individual components, since, among other things, the changes have advantages, properties such as the screen and the insulation are at best responsible. Acid addition salts and quaternary ammonium salts of the compounds in the mixtures form, as indicated above.

In the form of acid addition salts or quaternary ammonium salts The compounds, separately or in the mixtures formed in the reaction described, are interchangeable as antispasmodics. The acid addition salts also constitute valuable analeptics (central stimulants).

The mixture of N-ethyl-2-pyrrolidylmethyl-phenylcyclopentyl glycolate hydrochloride (68% by weight) and N-ethyl-3-piperidyl-phenylcyclopentylglycolate hydrochloride (32% by weight) is several times as strong antispasmodic, smodicum as atropine as isoline martin. The preparation also has a strong analeptic effect. animal.

The invention will be illustrated in the following by three non-limiting examples.

Example 1. Reaction of phenylcyclopentylglycolic acid with N-ethyl-3-chloropiperidine.

A mixture of 108.9 g, 0.50 moles, phenylcyclopentyl glycolic acid, 81.1 g, 0.55 moles of N-ethyl-3-chloropiperidine and 625 ml of isopropanol was boiled under reflux for 18 hours.

The solution was evaporated to dryness in vacuo on a water bath. The residue was dissolved in 11000 ml of water, pH 5, and extracted twice with 100 ml of ether. The ether extracts were discarded.

The aqueous solution was neutralized and quenched with sodium bicarbonate. The oil was separated from the aqueous layer, which was extracted three times with 200 ml of ether.

The combined ether extracts and oil were briefly dried over anhydrous magnesium sulfate. The ether and the boiling ingredients were distilled off using a water bath and water suction. Care must be taken to ensure that the free base is not heated above 100 ° C, since the pyrrolidylmethylene is converted to the 3-piperidyl compound when the free base is heated above 100 ° C. Complete rearrangement occurs at 170 ° C. The residue weighed 157 g, 95%.

The residue was dissolved in 350 ml of acetone and the bead was acidified with ethereal hydrochloric acid to pH 2. The precipitate was filtered off, washed with acetone and dried at 100 DEG C. Yield 111.5 g, 60.7%, mp 179181 DEG C. 91 g of the crude precipitate was recrystallized from 550 ml of acetonitrile, the solution being treated with tracol, clarified by filtration and crystallized at room temperature.

Infrared analysis showed that the product consisted of 68% by weight of N-ethyl-2-pyrrolidylmethylphenylcyclopentyl glycolate hydrochloride and 32% by weight of N-ethyl-3-piperidylphenylcyclopentylglycolate hydrochloride. The precipitate was isolated by filtration, mp 188-189 ° C, yield 52 g.

Analysis for C1-1ClNO3: Calculated: Cl 9.66% N 3.81% Found: Cl 9.65% N 3.80% Example 2. Reaction of N-ethyl 1-3 chloropiperidine with benzyl acid.

A mixture containing 44 g, 0.30 moles, of N-ethyl 1-3 chloropiperidine. and 68.4 g, 0.30 moles, of benzoic acid dissolved in 400 ml of isopropanol were boiled for 12 hours under reflux and then evaporated in vacuo to a yellow gum. This was dissolved in water and the basic esters were liberated by the addition of 55 g of potassium carbonate. The basic aqueous mixture was extracted with ether, then the ether extracts were dried over potassium carbonate and the ether was separated by filtration. The residual oil was converted to the hydrochloride salt in isopropanol with ethereal hydrochloric acid and the precipitate was filtered off, yielded, yield 100 g, 89%, mp 153-155 ° C. After recrystallization from 500 ml of isopropanol, 66 g of insoluble precipitate was obtained, containing 45% by weight of N-ethyl. 2-Pyrrolidylmethylbenzylate hydrochloride and 55% by weight of N-ethyl-3-piperidylbenzilate hydrochloride (hot infrared analysis), m.p. 163-167 ° C. Infrared analysis showed that it consisted of pure N-ethyl-2-pyrrolidylmethylbenzylate hydrochloride.

The precipitate, m.p. 163 DEG-167 DEG C., was recrystallized once from 150 ml of ethanol and the insoluble product was recrystallized from 75 ml of ethanol, yield 25 g, m.p. 191 DEG-192 DEG C. According to infrared analysis, this product was pure . N-ethyl-3-piperidyl-benzylate-hydrochloride.

Example 3. Preparation of N-ethyl-3-pyrrolidyl-methyl-phenyl-2-thienyl-glycolate, HCl.

A mixture of 0.033 mol of phenylthienyl glycolic acid, 4.85 g, 0.033 mol, N-ethyl-3-chloropiperidine and 25 ml of dry isopropanol was boiled for 24 hours under reflux. The reaction mixture was evaporated in vacuo, then the residue was suspended in water and acidified with dilute hydrochloric acid. After extraction with ether, the aqueous phase was neutralized with sodium hydride, after which the liberated base was extracted with ether. This was removed, after which the last remnants of the same and volatile burns were removed by keeping the residue at 100 ° C / 3 mm Hg.

The crude ester base thus obtained was dissolved in acetone and acidified with ethereal hydrochloric acid to give 3.3 g of crude salt, mp 167-171 ° C. After purification by recrystallization, 2 g of pure salt, mp 181-182 ° C, were obtained.

Analysis for C19H24ClNO3S: Calculated: Cl 9.30% N 3.67% Found: Cl 9.28% N 3.67% The embodiments described above can be modified without exceeding the scope of the invention.

Claims (5)

Patent claim: A compound of the formula O OH II 1/111 `11 2 R. in which R represents lower alkyl groups and phenyl lower alkyl groups, in which by" lower alkyl "is meant an alkyl group having 1-4 carbon atoms, saint R , and R, represent phenyl, 2-thien, γ1-, cyclohexyl or cyclopentyl groups, characterized in that a compound of the formula / \ / wherein X is a reactive halogen atom, is reacted with a compound of the formula OOH II 1/111 HO-C —C "F.2 under non-basic reaction conditions. 2. Set according to patent claim 1, characterized in that a. N-lower alkyl-1-3-halopiperidine. 4: 2046 was reacted with phenyl-cyclopentyl-glycolic acid to give Ebbing an N-lower alkyl-2-pyrrolidylmethylphenylcyclopentyl glycolate. 3. A sieve according to claim 1, characterized in that N-ethyl-3-chloropiperidine was saturated with phenylcyclopentyl-glycolic acid to form Nethyl-2-pyrrolidylmethyl-phenyl-cyclopentylglycolate. 4. A kit according to claim 1, characterized in that N-1-lower-alkyl-3-halopiperidine is reacted with, with, benzylic acid to give a 1'-agaralkyl-2-pyrrolidylmethyl-benzylate. 5. Juice according to claim 1, characterized in that N-ethyl-3-chloropiperidine is reacted with benzyl acid to form N-ethyl-2-pyrrolidyl-methylbenzylate. Request publications: Pateritskrifter tram USA 2 695 301, 2 928 843.