NO117063B - - Google Patents

Description

The formula in the patent claim is set up incorrectly in the patent document. It should read:

Process for the production of carbamates.

The present invention relates to a

process for the preparation of carbamates of tertiary carbinols and more particularly a process for the preparation of carbamates of tertiary acetylenic carbinols, which are useful for producing hynosis in animals and/or for protecting them from convulsive seizures.

The compounds produced in accordance with the method according to the invention can be designated as carbamates of ethynyl-tertiary carbinols in accordance with the following structural formula:

where R is an alkyl group with 1 to 8 carbon atoms, alkenyl or haloalkenyl group with from 2 to 8 carbon atoms; R' is an alkyl group with from 1 to 7 carbon atoms, preferably an ethyl group; and R'' is hydrogen, an alkyl group with from 1 to 6 carbon atoms, or halogen, preferably chlorine or bromine.

A class of vinylethynyl tertiary carbinols has been found to be highly effective hypotensive and/or consulative agents. These compounds mostly occur in a liquid state and are therefore most conveniently administered in capsule form. However, re-encapsulation of diluted pharmaceutical products is an expensive process, and should therefore be avoided as much as possible.

It has now been shown that carbamates of vinylethinyl tertiary carbinols as mentioned above retain the high activity that the carbinols exhibit, and furthermore they occur in a solid state, whereby they are particularly suitable for tableting instead of encapsulation as with the liquid substances. Furthermore, these carbamates show low toxicity when administered to animals for toxicity testing. These properties make the substances particularly advantageous as hypnotic and anticonvulsant agents.

The vinylethynyl tertiary carbamates according to the invention can be designated by the following structural formula:

where R is hydrogen or an alkyl group

with from 1 to 6 carbon atoms, R' is an alkyl group with from 1 to 7 carbon atoms, preferably an ethyl group, R" is hydrogen, an alkyl group with from 1 to 6 carbon atoms, or halogen, preferably chlorine or bromine, and X is halogen, preferably chlorine or bromine.

The presence of a halogen atom

(X) at the terminal vinyl carbon atom appears to give these compounds an exceptionally high hypnotic activity. Although derivatives of this kind, where R' is a methyl group, are very useful in this respect, we have found that those compounds where R' is ethyl are particularly useful.

We have found that all the usual methods for preparing carbamates with tertiary acetylenic carbinols fail, which is largely due to the ease with which they are dehydrated. In our first experiments with methyl vinylethynyl carbinol, furthermore, the highly unsaturated nature of this carbinol led to further complications and it was not surprising that all the methods that were first tried did not lead to satisfactory results.

Treatment of methyl-vinyl-ethynyl carbinol (in excess) with cyanic acid (from cyanuric acid) gave e.g. in the essential allophanate, and although a small amount of karbamate was possibly formed, we were unable to separate this from the less soluble allophanate. Reaction of the same carbinol with potassium cyanate and acetic acid evidently led to a strong dehydration or rearrangement of the molecule, and no carbamate could be isolated. Ester exchange between methyl vinyl ethynyl carbinol and ethyl carbamate (urethane) in the presence of sodium ethoxide was slow and incomplete and of the carbinol thus treated no carbamate could be detected in the recovered ethyl carbamate. The conversion of this carbinol to the mixed carbonate with ethyl chloroformate in pyridine, and treatment of this carbonate with ammonia (gas or aqueous-alcoholic or lithium amide) still only led to the recovery of the carbonate. The infrared spectrum of the recovered mixed carbonate gave no signs of carbamate formation.

Two of them. synthetic methods that are reproduced in the literature are believed to be particularly applicable to tertiary carbinols. In accordance with one of these methods, addition of carbamyl chloride to a pyridine solution of methyl vinylethynylcarbinol led to a vigorous reaction and precipitation of pyridine hydrochloride. However, in a series of experiments only the carbinol could be recovered. Furthermore, the yield of recovered carbinol was poor, and the infrared spectrum showed no trace of carbamate. In one experiment, a very small amount of solid was isolated, but this proved to be the allophanate of the treated carbinol. The other method believed to be beneficial with simple tertiary alcohols involves the conversion of the alcohol to its chloroformate ester with phosgene at low temperature and in the presence of a tertiary amine, followed by treatment of the chloroformate with ammonia. This method was applied to methyl-vinyl-ethynyl-carbinol and to related carbinols in a large number of experiments. Not. however, in some cases significant precipitation of amine hydrochloride occurred, even at significantly higher temperatures than those recommended in the literature. Some carbinol was always recovered, and after treatment with ammonia nothing more than traces of carbamate could be detected.

However, we have found that the above class of carbamates can be easily prepared by treating a tertiary carbinol of the general formula:

where R, R', R" are as defined above, with an aromatic chloroformate to form the corresponding aromatic carbonate, followed by treatment of the carbonate with ammonia. The ethynyl tertiary carbinols can in turn be prepared by treatment of an appropriate ketone , i.e. an alkyl, alkenyl, haloalkenyl ketone with an alkali metal salt of an acetylenic compound, as described above. Particular examples of such carbinols are: methyl-beta-chlorovinyl-ethynyl-carbinol ethyl-beta-chlorovinyl-ethynyl -carbinol propyl-beta-chlorovinyl-ethynyl-carbinol hexyl-beta-chlorovinyl-ethynyl-carbinol

heptyl-betachlorovinyl-ethynyl-carbinol methyl-beta-chloropropenyl-ethynyl-carbinol ethyl-beta-chloroctenyl-ethynyl-carbinol propyl-beta-chloroheptenyl-ethynyl-carbinol butyl-beta-bromobutenyl-ethynyl-carbinol hexyl-beta-bromopentenyl-ethynyl -carbinol heptyl-beta-bromohexenyl-ethynyl-carbinol methyl-beta-chlorovinyl-propynyl-carbinol ethyl-beta-chlorovinyl-butynyl-carbinol propyl-beta-chlorovinyl-octynyl-carbinol dimentyl-ethynyl-carbinol methyl-ethyl-ethynyl-carbinol ethyl-propyl-ethynyl-carbinol propyl-butyl-ethynyl-carbinol heptyl-octyl-ethynyl-carbinol methyl-vinyl-ethynyl-carbinol

ethyl-vinyl-ethynyl-carbinol isopropyl-hexenyl-ethynyl-carbinol n-propyl-octenyl-ethynyl-carbinol

In accordance with the present invention, the aromatic chloroformate is added to a solution of the tertiary carbinol in the presence of a tertiary organic base, preferably one which also acts as a solvent. Suitable bases include triethylamine, dimethylaniliri, coal tar booths, such as e.g. pyridine, picolines, hollidines, lutidines, quinolines and substituted quinolines, and mixtures thereof. The base is used in an amount which is sufficient to combine with the hydrogen chloride, which is released by the reaction between the tertiary carbinol and the chloroformate, at least one mole of base per mol. mol carbinol is preferred for obtaining the best results. The following should be mentioned as typical representatives of the aromatic chloroformates: phenyl chloroformate, alkylated phenyl chloroformate, chlorophenyl chloroformate, nitrophenyl chloroformate, alpha-naphthyl chloroformate, beta-naphthyl chloroformate and the like. The reaction is preferably carried out under anhydrous conditions during cooling and a reaction time of from 2 to 5 hours is sufficient in most cases. By adding water, the aryl carbonate of the tertiary carbinol can be extracted with a water-immiscible solvent, such as ether, chloroform, cyclohexane, benzene and the like. After several extractions of the carbonate with the solvent, the solvent extracts can be combined and washed with an appropriate mineral acid, such as hydrochloric or sulfuric acid, to remove excess base from the solution, followed by a saturated solution of a salt, such as sodium chloride or sodium sulfate , and containing an excess of sodium bicarbonate to neutralize and partially dry the combined extracts. The solution containing the aryl carbonate of the ethynyl tertiary carbinol is then suitably dried with a suitable drying agent, such as anhydrous magnesium sulfate, and then filtered. The resulting solution can be used directly for the preparation of the carbamate or it can be concentrated to give the crude aromatic carbonate of the tertiary carbinol. The intermediate carbonates produced in this way can be represented by the following structural formula:

where R, R' and R'' have the same meaning as previously indicated, and R'' is an aromatic or substituted aromatic group.

The desired carbamates are preferably produced by treating the above-mentioned aromatic carbonates with ammonia, i.e. without isolating the carbonate. In this connection, different methods can be used. For example can ammonia be bubbled slowly through a solution, e.g. an ether solution of the aromatic carbonate at room temperature in 8a. 10-12 hours to convert the latter into the corresponding carbamate. Alternatively, the ether solution of the crude aromatic carbonate is added to liquid ammonia and allowed to react for 10 to 24 hours, while the ammonia is allowed to evaporate slowly under reflux. This method is preferred for obtaining the best results. In yet another method, the ether solution of aromatic carbonate prepared as stated above can be concentrated and bp treated with saturated ethanolic ammonia and the resulting mixture allowed to stand at room temperature for approximately the same time as mentioned above to complete the reaction.

In all of the methods described above, the resulting carbamate can conveniently be taken up in water and ether, and extracted with further ether to remove the desired product from by-products and impurities. The ether extract can then be washed with sodium hydroxide solution to remove the phenolic by-products from the reaction, after which it is washed with saturated sodium chloride solution. The ether solution is then dried and concentrated to a small volume. The addition of petroleum ether then precipitates the carbamate, which is obtained as a white solid. It can be easily recrystallized from a mixture of ether and petroleum ether for further purification.

The method according to the invention shall be further clarified by means of the following examples. The invention is, as will be understood, not limited to the examples listed here.

Example 1: Phenyl carbonate of ethyl-beta-.chlorovinyl- ethynyl carbinol. 39 g of phenyl chloroformate (0.249 mol) was added dropwise to a stirred, ice-cooled solution of 39.6 g of ethylbeta-chlorovinyl-ethynyl-carbinol (0.274 mol) in 100 mil of anhydrous pyridine. Then the suspension of the solid was stirred under cooling for 2-3 hours. 150 ml of water and 150 ml of ether were added, and the aqueous layer was extracted with several fresh portions of ether. The combined ether extracts were washed with 300 ml of cold 18% hydrochloric acid in two portions and finally with saturated sodium chloride solution containing excess sodium bicarbonate. The ether layer was dried with anhydrous magnesium sulfate and filtered. At this point the ether solution can be used directly for the preparation of the carbamate or it can be concentrated to give the crude phenyl carbonate of ethyl beta- chlorovinyl ethynyl carbinol.

Example 2:

Ethyl beta-chlorovinyl carbamate ethynyl carbinol.

Ammonia was bubbled slowly over 8 hours through an ether solution of phenyl carbonate of ethyl-beta-chlorovinyl-ethynylcarbinol prepared as indicated in Example 1 from 6.6 g of carbinol. Although a condenser was used, most of the ether was lost during this treatment. The reddish semi-solid residue was taken up in water and ether was added, and the aqueous layer was extracted several times with ether. The combined ether extracts were washed twice with 50 ml portions of 2.5% sodium hydroxide solution and finally with saturated sodium chloride solution. The ether solution was dried with anhydrous magnesium sulfate, then concentrated to a low volume and diluted with petroleum ether. The carbamate was precipitated at this point as a white solid, which was recrystallized from ether-petroleum ether to give 5.2 g of colorless leaves with a melting point of 98.5-99.5° C. A further 0.3 g was obtained from the filtrate . Yield 5.5 g. (64 per cent of the carbinol.) The analytical sample was recrystallized from methanol-water as heavier crystals, melting point 98.5-99.5° C.

Analysis:

Calculated for: C8HI0O2<N>Cl: wt C, 51.21; psi H. 5.37; pst N, 7.47.

Found: pst C, 51.43; station H, 5.40; pst N, 7.42.

Example 3:

Ethyl beta-chlorovinyl carbamate ethynyl carbinol.

1700 ml of an ether solution of the crude phenyl carbonate from 39.0 g of ethyl-beta-chlorovinyl-ethynyl-carbinol, prepared as in ex. I, was added to 2500~ ml of liquid ammonia and held at the reflux temperature of the mixture for 6.5 hours. Ammonia was allowed to evaporate overnight with stirring. The remaining solution was treated as in Example II and the carbamate was obtained as 3389 g (65.8% yield) of colorless leaves, m.p. 100— 101.2° C.

Example 4:

Ethyl beta-chlorovinyl carbamate ethynyl carbinol.

The crude phenyl carbonate of 19.8 g of ethyl-beta-chlorovinyl-ethynyl-.carbinol, obtained by

careful concentration of an ether solution, prepared in accordance with

example I, was taken up in 100 ml of saturated ethanolic ammonia and left to stand at room temperature overnight. The red solution obtained was concentrated under mild conditions and the carbamate was obtained as in Example II. The yellowish crystals weighed 10.9 (42.4% yield) and had m.p. 97-98° C.

Example 5:

Ethyl beta-chlorovinyl carbamate ethynyl carbinol.

13.1 g of methyl beta-chlorovinyl-ethynyl-carbinol (0.10) mol was treated in accordance with Example I to form the corresponding carbonate of the methyl homologue. The crude phenyl carbonate thus formed was then added to liquid ammonia as in Example III to convert the intermediate mixed carbonate to the carbamate. After treatment of the remaining solution as in example II, the desired carbamate was obtained in an amount of 8.38 g (48.3% yield), m.p. 92.9—93° C.

Analysis:

Designed for: C7H802NC1: pst.C,

48.43, pst.H, 4.65, pst.N, 807.

Found:

pst.C; 48.25, pst.H, 4.70, pst.N, 807.

Example 6:

Carbamate of n-propyl beta-chlorovinyl- ethynyl-carbinbl.

15.9 g of n-propyl beta-chlorovinyl-ethynyl-carbinol (0.10 mol) was treated as in es-

sample 5 to obtain 5.86 g (29.1% yield) of the corresponding carbamate, m.p. 63.9 — 64.8° C.

Analysis:

Calculated for: C9H1202NC1: pst.C, 53.60, pst.H, 6.00, pst.N, 6.95.

Found: pst.C, 53.62, pst.H, 6.11, pst.N, 6.93.

Example 7: Carbamate of i-propyl-beta-chlorovinyl- ethynyl carbinol.

In accordance with the procedure according to Example 5, 15.9 g of i-propyl-beta-chlorovinyl-ethynyl-carbinol (0.10 mol) were used to prepare 1.3 g of the corresponding carbamate (6.5% yield), m.p. 91-92° C.

Analysis:

Calculated for: CflH12O2<N>Cl: pst.C, 53.60, pst.H, 6.00, pst.N, 6.95.

Found: pst.C, 53.61, pst.H, 5.90, pst.N, 7.17.

Example 8:

Carbamate of methyl-ethyl-ethynyl- carbinol.

9.8 g of methyl-ethyl-carbinol (0.10 mol) was treated according to Example 5 to obtain 3.0 g (21.2% yield) of the corresponding carbamate, m.p. 55.8—57° C.

Analysis:

Calculated for: C7Hn02N: pst.C,

59.55, pst.H, 7.85, pst.N, 9.92.

Found: pst.C, 59.40, pst.H, 7.75, pst.H, 9.67.

Example 9:

Carbamate of methyl-vinyl-ethynyl- carbinol.

19.2 g methyl-vinyl-ethynyl-carbinol (0.20

mol) was treated in accordance with the procedure in Example V to obtain 19.9 g (71.6% yield) of the corresponding carbamate, m.p. 56.6—57.4° C.

Analysis:

Designed for: C7H902N: pst.C,

60.42, pst.H, 6.52, pst.N, 10.07.

Found: • pst.C, 60.41, pst.H, 6.60, pst.N, 10.16.

Example 10:

Carbamate „of ethyl-vinyl-ethynyl- carbinol.

16.5 g of ethyl-vinyl-ethynyl-carbinol (0.15 mol) was treated according to eq.

sample 5 to obtain 12.7 g (55.2 percent yield) of the corresponding carbamate, m.p. 39.2 — 40° C.

Analysis:

Designed for: C8Hu02N: <p>st.C,

62.72, pst.H, 7.24, pst.N, 9.15.

Found: pst.C, 62.46, pst.H, 7.12, pst.N, 9.16.

Example 11:

Carbamate of isopropyl-vinyl-ethynyl- carbinol.

10.1 g of isopropyl-vinyl-ethynyl-carbinol (0.081 mol) was treated in accordance with Example 5 to obtain 3.4 g (25.0% yield) of the corresponding carbamate, m.p. 44.5 — 45.5° C.

Analysis:

Calculated for: C9Hn02N: pst.C,

64.65, pst.H, 7.83, pst.N, 8.38.

Found: pst.C, 64.41, pst.H, 7.72, pst.N, 8.43.

Example 12:

Carbamate of methyl-ethyl-chloroethynyl- carbinol. 13.3 g of methyl-ethyl-chloroethynyl-carbinol (0.10 mol) was treated in accordance with example 5 to obtain 2.95 g (16.8% yield) of the corresponding carbamate, m.p. 98 — 99° C.

Analysis:

Calculated for C7H10O2NCl: pst.C,

47.87, pst.H, 5.74, pst.N, 7.98.

Found: pst. C, 47.94, pst. H, 5.79, pst. N, 8.00.

In general, the carbamates of this invention are white solids, which are well suited for therapeutic purposes. Marked hypnosis was observed in animals to which the substance was administered, and the compounds have been shown to protect such animals effectively against convulsive seizures. This enables treatment of animals that would otherwise not be possible without the use of a hypnotic agent. As previously pointed out, the toxicity of the compounds has been shown to be low, and no harmful pharmacological effects have been observed as a result of the administration of the substances.

The above-mentioned compounds can be used in large numbers in different medical dosage methods, i.e. they can be introduced into different inert pharmaceutical carriers, such as e.g. solid diluents, oils etc., or together with biologically active materials in the form of tablets, capsules, drinks, injectable solutions and the like.

Because they are solids, they are particularly suitable for the production of tablets for oral administration. In general, the oral dosage forms can be sweetened and flavored with various substances of the type normally used for this purpose.

When the compounds are used in such medicinal dosage forms, they may be present in concentrations varying from approx. 0.5% by weight to approx. 90% by weight of the composition. Lower concentrations are generally not advisable, as the volume of the material that must be administered then becomes far too large.

Finally, it should be noted that from French patent no. 1,075,385 it is known to prepare various substituted carbamates by treating tertiary carbinols with an isocyanate of the formula R3NCO. The starting materials specified in the patent document also comprise a part of the carbinols mentioned in the present method, but the present method differs from the known one in that an isocyanate is not used in the method according to the present invention. Furthermore, the products according to said patent are substituted carbamates, where R3 is an aliphatic group that replaces hydrogen in the amine group. In the compounds according to the present invention, there are no substituents in this position.

Attention should also be drawn to the French patent no. 1,079,916 which relates to a method known in the art for the production of carbamic acid esters of aikohoia, of a different kind than those described in the present claim, and their corresponding carbamates. The method according to the present invention for the production of esters or their corresponding carbamates is, however, new. It should also be noted that in the introduction to this description the previously known methods to which the said patent relates are mentioned, and it is also clear from what is stated in this description that the present method differs directly from the previously known methods and represents an advance directly opposite these.

Claims (1)

Process for the production of carbamates which are effective hypnotic or convulsive agents in the solid state, characterized in that a compound with the following formula: where R is an alkyl group with from 1-8 carbon atoms, alkenyl or haloalkenyl group with from 2-8 carbon atoms, R' is an alkyl group with from 1-7 carbon atoms, preferably an ethyl group and R" is hydrogen, an alkyl group with from 1-6 carbon atoms, or halogen, preferably chlorine or bromine, are reacted with an aromatic chloroformate, preferably phenylchloroformate, and that the carbonate formed, preferably without isolation, is reacted with ammonia to the corresponding carbamate.