DE1768925A1 - 2,2-disubstituted-2-cyanoaethanols - Google Patents

Description

2,2-Disubstituted-2-Cyanoethanols The present invention relates to certain new 2,2-disubstituted-2-cyanoethanols, their production, their conversion in derivatives including 1-amino-2,2-disubstituted-propanol and 5,5-disubstituted-tetrahydro-2H, 1,3-oxazin-2-ones and the use of these compounds as active ingredients in pharmaceutical preparations.

The tetrahydrooxazinones mentioned are physiologically active substances, which are known, among other things, from the French medical patent specification No. 1626 M., U.S. Patent No. 2,940,971 and British Patent No. 931 571. Die cyanoethanols and aminopropanols mentioned are useful intermediates in the manufacture the tetrahydrooxazinone.

The present invention relates, inter alia, to an improved method of manufacture for the tetrahydrooxazinones mentioned.

The present invention accordingly provides a process for the preparation of compounds of the general formula wherein R1 and R2 stand for an aryl group and an alkyl group, respectively, characterized in that formaldehyde with a compound of the general formula wherein R1 and R2 have the same meaning as above, is condensed in an inert reaction medium in the presence of a catalytic amount of a strongly basic quaternary ammonium hydroxide or alkoxide.

The reaction medium can advantageously be toluene or a lower alkanol, which preferably contains 1-4 carbon atoms, for example methanol or Ethanol can be used. The reaction medium can also contain water (where the formaldehyde in the form of an aqueous solution as well as in the form. can not be applied may) .. However, it is preferred the inert solvent in such a proportion apply that the reaction medium is homogeneous at the beginning of the reaction.

Examples of quaternary ammonium catalysts suitable for the procedure which can be used according to the invention are N-benzyltrimethylammonium methoxide (in this case, a suitable solvent for the reaction is for example also benzene) N-benzyltrimethylammonium hydroxide, tetramethylammonium hydroxide, tetraethylammonium hydroxide and tetra-n-butylammonium hydroxide.

It is of particular importance that none or at least one very poor yield of the desired product can be obtained when used as a catalyst such basic reagents instead of the special quaternary ammonium compounds such as sodium ethoxide, calcium oxide, Deacidite PF ion exchange resin ("Deacidite" is a registered trademark), sodium hydroxide or piperidine can be used. This is the opposite of what has been experimentally found in the prior art when the base-catalyzed condensation of formaldehyde with a -OH20CN group instead of a \ CH. CN group was attempted.

The aromatic group R1 can have one or more substituents in the nucleus be substituted that do not interfere with the desired reaction. Examples these include alkyl or alkoxy substituents and halogen substituents such as chlorine, Bromine or iodine. Any alkyl or alkoxy substituents may be advantageous each contain 1-4 carbon atoms. Examples are irjethyl, ethyl, propyl, Isopropyl, butyl, s-butyl, t-butyl, Methoxy, ethoxy, isopropoxy, Isobutoxy, butoxy or t-butoxy.

The alkyl group R2 is preferably saturated. It can be up to b or contain even more carbon atoms and preferably contains 1-4 carbon atoms. It can be substituted by tertiary amino or alkoxy groups.

Examples are methyl, ethyl, dimethylaminoethyl, propyl, Ethoxypropyl, isopropyl, diethylaminobutyl, t.-butyl, amyl, sec.amyl, methoxyamyl, Hexyl, heptyl or octyl.

W-phenylbutyronitrile is advantageously used as the starting product of the formula II (i.e. R1 is phenyl and R2 is methyl) is used.

The products of the formula I are new compounds and valuable intermediates, which as such also form part of the subject matter of the present invention. They are usually crystalline solids that crystallize on standing. They can be distilled under reduced pressure.

The products of the formula I can thereby be removed from the reaction mixture obtained that the reaction mixture "flooded" with water, extracted with ether, the ether extract dried over MgS04, the ether was distilled off and the residue distilled in vacuo to give a liquid which soon crystallizes. When toluene is used as the reaction medium, the reaction mixture washed and dried, and the toluene is distilled off. The addition of petroleum ether with stirring causes the desired product to precipitate.

According to one embodiment of the present invention, the product of the formula I is reduced, for example by catalytic hydrogenation, expediently over Raney nickel or by the action of lithium aluminum hydride in diethyl ether or tetrahydrofuran, a 1-amino-2,3-disubstituted-propanol of the general formula where R1 and R2 have the same meaning as in J? onel I, is obtained. According to another embodiment according to the present invention, the compound of the formula III obtained is converted into a tetrahydrooxazinone compound of the general formula where R1 and R2 have the same meaning as in formula 1, converted by reaction with phosgene in an inert solvent (as in the USA patent specification no.

2,940,971), or by condensation with a Dialkyl carbonate in the presence of an alkaline catalyst (e.g. sodium methoxide), or with a Diaryl carbonate, the two molecules being split off, for example, by distillation Alkanol or phenol can be removed. Examples of carbonates that are used are diphenyl carbonate, diethyl carbonate (as in British Patent No. 931 571) and dimethyl carbonate.

While, according to the prior art, the compounds of the formula IV Central nervous system stimulants and barbiturate antagonists Now found that they are actually depressants for the central nervous system and potentiate the barbiturates. It has also been found to be useful have analgesic and antispasmodic effects.

The present invention also relates to a method for producing an analgesia, which is characterized in that a pain sufferer Animal an analgesically effective, non-toxic dose of about 10-1000 mg of a compound of the formula IV, in which R1 is an alkyl group and R2 is a phenyl group, administered is, or the use of the compound of formula IV mentioned as an analgeic Active ingredient.

In the analgesic treatment according to the invention, the substituent is R1 is preferably a lower alkyl group having 1-4 carbon atoms, for example Methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or t-butyl. The substituent R2 can be an unsubstituted or a substituted phenyl group be. Substituents on the phenol group can, for example, be hydroxyl, trifluoromethyl, lower alkyl groups with 1-4 carbon atoms such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or t-butyl, lower alkoxy groups with 1-4 carbon atoms such as methoxy, ethoxy, n-propyloxi, isopropyloxi, n-butoxy, isobutoxy or t-butoxy and halogen atoms such as chlorine, bromine and fluorine. R1 is particularly preferably a Ethyl group and R2 for the phenyl group.

The compound is preferably used in a dose of 10-510 mg, especially administered preferably from 45-360 mg and very particularly preferably from 90-210 mg. The administration can of course take place once or several times a day, as is the case with the use of analgesics is known.

It is particularly advantageous if the compound is administered orally.

They have been found to be at analgesic dose levels exhibits essentially no irritating effect on digestion. She can too Administered rectally or parenterally. Depending on the route of administration and Each dose will typically range from 0.1 mg / kg to the animal to be treated about 150 mg / kg. In adult humans, an analgesic effective dose may be used when administered orally, be between about 1 mg / kg and 15 mg / kg. In the treatment of lower animals one can Dose of 30 mg / kg to 150 mg / kg required be. The compound is normally used as an active ingredient in a manner known per se with one or more pharmaceutical diluents or carriers processed into pharmaceutical preparations, preferably into a so-called Unit dose form such as a tablet, a capsule, a suppository, a Cachet, a butyl, an olfactory pad or the like. Furthermore, such preparations other active ingredients, especially mild analgesics and anti-inflammatory drugs Contain agents such as aspirin.

The following examples illustrate the present invention.

Example 1:; -Phenylbutyronitrile (14.5 g, 0.1 mole), paraformaldehyde (6.0 g, 0.2 mol), 25% aqueous tetramethylammonium hydroxide solution (5 ml, 0.01 Mol) and ethanol (67 ml) were heated together under reflux for 48 hours. The mixture was then allowed to cool and poured into 600 ml of water. The product was extracted with ether. The essential extract was made with dilute hydrochloric acid washed until free of catalyst. Then was made with aqueous sodium bicarbonate washed and dried with magnesium sulfate. The ether was on a water bath distilled off, and the residue was distilled under reduced pressure, whereby the d-hydroxymethyl - $ - phenylbutyronitrile at 1220C / 0.8 mm as a viscous colorless oil distilled, which turns to a white crystalline on standing Solidified plague bodies with a melting point of 64-66 ° C. Yield: 9.7 g (55.4% of theory). Found: C, 75.51; H 7.60; N, 7.91 7a 'C11H13ON calculated: C, 75.43; H 7.43; N 8.0 % Examples 2-5: Example 1 was repeated, but instead of the tetramethylammonium hydroxide aqueous tetraethylammonium hydroxide, aqueous tetra-n-butylammonium hydroxide, aqueous Benzyltrimethylammonium hydroxide or methanolic benzyltrimethylammonium methoxide was used as a catalyst with the following success: Catalyst Yield Aqueous Tetraethylammonium hydroxide 61, 2% aqueous detra-n-butylammonium hydroxide 57.1 % aqueous benzyltrimethylammonium hydroxide 57% methanolic benzyltrimethylammonium methoxide 65.1% Examples 6-9: Example 1 was repeated, but instead of ot-phenylbutyronitrile α-phenylpropionitrile, α-phenyl-β-methylbutyronitrile, α- (p-methoxyphenyl) butyronitrile respectively.

α- (m-Chlorophenyl) butyronitrile was used. The following Results were obtained: Products Nitril K.p. F. p. yield ct-phenylpropionitrile 120 / 1mm Db% α-phenyl-ß-methylbutyronitrile 100 / 0.05mm 44% α- (p-methoxyphenyl) butyronitrile 152 / 1.1 mm 45-46 ° C 45% - (m-chlorophenyl) butyronitrile 113 / 0.02mm 35% Example 10: α-Phenylbutyronitrile (14.5 g), paraformaldehyde (6.0 g), 40% methanolic benzyltrimethylammonium methoxide (32 ml) and benzene (67 ml) was refluxed for 48 hours. The mixture was then cooled and poured into 600 ml of water. The upper organic layer was separated, washed with dilute hydrochloric acid until it was free of catalyst, and then with washed aqueous sodium bicarbonate solution. Then was with magnesium sulfate dried. The drying agent was filtered off and the filtrate was reduced under reduced pressure Pressure fractionally distilled, whereby 10 g (57.1 of theory) of α-hydroxymethyl-α-phenylbutyronitrile, F .p. 65-66 ° C was obtained.

Example 11: α-Phenylbutyronitrile (80 g), 40% strength aqueous formaldehyde solution (164 g), 40% aqueous benzyltrimethylammonium hydroxide (17.2 ml), and ethanol (300 ml) was refluxed for 48 hours. The mixture was then cooled and poured into 3 liters of water. The product was obtained as described in Example 1 and cleaned. The yield of α-hydroxymethyl-α-phenylbutyronitrile was 32 g (33 ffi of theory), melting point 64-660C.

Example 12: α-Phenylbutyronitrile (492 g, 3.4 mol), paraformaldehyde (204 g, 6.8 mol), 265 "oiges methanolic benzyltrimethylammonium methoxide (214 ml, 0.34 mol) and toluene (1500 ml) were refluxed together for 36 hours. The cooled reaction mixture was successively with water (2 1), 1oaiger hydrochloric acid (1 1), water (1 1), 5% aqueous sodium bicarbonate (1 L) and water (twice 2 1), washed and then dried with magnesium sulfate. The toluene was on a Removed steam bath under reduced pressure. When adding petroleum ether (boiling point 40-60 ° C) 1.5 1) and stirring for one hour was the precipitation of α-hydroxymethyl-α-phenylbutyronitrile caused as a white crystalline mass. This was collected and dried.

Melting point 64-660 ° C. The yield was 508 g (85.4% of theory) of example 13: α-Hydroxymethyl-α-phenylbutyronitrile (635 g) g) in methanol (650 ml) was hydrogenated in a stainless steel rocking autoclave, with 5% Raney nickel was used as a catalyst. In the autoclave was then hydrogen up to A pressure of 100 atmospheres was initiated, and then the temperature was increased to 100 ° C heated. The hydrogen intake had ceased after 6 hours. The autoclave was then cooling down left, opened, and the catalyst from the reaction mixture filtered off. The methanol was distilled off and the residue was reduced under reduced pressure Pressure fractionally distilled. The product, the 2-hydroxymethyl-2-phenylbutylamine was collected at 120 ° C / 0.5 mm.

Yield: 470 g (72% of theory).

Example 14: 2-hydroxymethyl-2-phenylbutylamine (58.5 g) and diphenyl carbonate (47.2 g) were mixed together in a still. An exotherm occurred Response a.

The mixture was then heated to 160 ° C in an oil bath and the pressure was reduced until the liberated phenol distilled off. After the whole liberated phenol was removed, the mixture was cooled and dissolved in ethyl acetate solved. Petroleum ether (K.p. 60-bO 00) was added to this in order to precipitate a viscous oil, that crystallized when standing. This solid was collected and made from toluene recrystallized, white crystals of 5-thyl-F. p. 103-104 ° 0 5-phenyl-tetrahydro-2H, 1, 3-oxazin-2-one.

Yield: 35.8 g (53.5% of theory).

The following examples illustrate the manufacture of pharmaceutical Preparations for the purposes of the present invention. Reference is made here to some preferred compounds to illustrate the invention for example.

Example 15: Tablet production mg / tablet of 5-ethyl-5-phenyl-tetrahydro-1,3-oxazin-2-one 15 lactose d6 corn starch (dried) 45.5 gelatin 2.5 magnesium stearate 1.0 das Fi 5-ethyl-5-phenyltetrahydro-1, 3-oxazin-2-one was pulverized and through a B.S. No. 100 sieve driven.

It was then mixed well with the lactose and 30.mg of the corn starch, both of which are supported by a B.S. No. 44 sieve had been driven.

The powder mixture was made into a paste with a warm gelatin solution, which was made by stirring the gelatin in water and heating it to make a 10 wt% solution. The mass was granulated that they are through a B.S. No. 12 sieve was driven. The moist granules were at 40 ° C dried.

The dried granulate was granulated again by passing it through a B.S. No. 14 sieve was driven. The rest of the starch sifted on 44 mesh and the magnesium stearate sieved to 60 mesh was added and mixed in thoroughly.

The granules were compressed into tablets, each weighing 150 mg.

Example 16: Tablet production mg / tablet of 5-ethyl-5-phenyltetrahydro-1,3-oxazin-2-one 100 lactose 39 corn starch (dried) 80 gelatin 4.0 magnesium stearate 2.0 Das Manufacturing process was identical to that of Example 15 with the modification that 60 mg of strength for the granulation process and 20 mg during tableting were used.

Example 17: Capsule production mg / tablet 5-ethyl-5-phenyl-tetrahydro-1,3-oxazin-2-one 50 Lactose 150 The 5-ethyl-5-phenyltetrahydro-1,3-oxazin-2-one and the lactose were by a No. 44 B.S. Sieve driven. The powders were mixed well before using them were filled in hard gelatin capsules of appropriate size so that each capsule Contained 200 mg of the powder mixture.

Example 18: Suppositories mg / suppository 5-ethyl-5-phenyl-tetrahydro-1,3-oxazin-2-one 50 Cocoa Butter 950 The 5-ethyl-5-phenyltetrahydro-1 5-oxazin-2-one was pulverized and through a B.S. No. 100 sieve driven. Then it was melted with Cocoa butter at 45 ° C treated to make a smooth suspension.

The mixture was stirred well and poured into molds, each of which nominally 1 g in size to make suppositories.

Example 19: Cachets mg / Cachet 5-ethyl-5-phenyl-tetrahydro-1,3-oxazin-2-one 100 Lactose 400 The 5-ethyl-5-phenyltetrahydro-1, soxazin-2-one was obtained by a B.S. No. 40mesh sieve driven and mixed with the lactose previously made to 44 mesh was sifted. The powder mixture was filled into cachets of appropriate size, so that each contained 500 mg.

Example 20: Intramuscular Injection (suspension in an aqueous Medium): 5-ethyl-5-phenyltetrahydro-1,3-oxazin-2-one 10 mg sodium citrate 5.7 mg sodium carboxymethyl cellulose (Low viscosity type) 2.0 mg methyl para-hydroxybenzoate 1.5 mg propyl para-hydroxybenzoate 0.2 mg water for injection up to 1.0 ml The sodium citrate and the sodium carboxymethyl cellulose were given a sufficient amount of water for injection at 80 ° C mixed together. The mixture was cooled to 50 ° C. Then it became Methyl and propyl parahydroxybenzoate and then 5-ethyl-5-phenyltetrahydro-1,3-oxazin-2-one added. Both products were previously ground and sieved to 300 mesh. After this To cool down, the injection solution was made up to the desired volume and washed through Sterilized by heating in an autoclave.

Example 21: Suspension for Oral Administration Glycerin 1.0 g tragacanth resin 0.2 g 5-ethyl-5-phenyltetrahydro-1, 3-oxazin-2-one 2 g tartaric acid 0.85 g Syrup B.P. 30.0 ml concentrated peppermint water B.P. 3.0 ml of soluble methyl para-hydroxybenzoate 0.0d g of soluble propyl para-hydroxybenzoate 0.025 g of distilled water up to 1040 ml The tragacanth resin was moistened with the glycerine. The tartaric acid was Dissolved in 60 ml of distilled water, uni the preservatives and the moistened Tragacanth resin was added. This was followed by the syrup and the flavorings incorporated, and then 5-ethyl-6-phenyltetrahydro-1,3-oxazin-2-one added which was previously ground and sieved to 300 mesh. The mixture was with distilled water made up to the desired volume and homogenized. Claims

Claims (22)

Claims: 1. Process for the preparation of compounds of the formula in which R1 and R2 each represent aryl or alkyl radicals, characterized in that formaldehyde is combined with a compound of the formula where R1 and R2 have the same meaning as in formula I, condensation is carried out in an inert reaction medium in the presence of a catalytic amount of a strongly basic quaternary ammonium hydroxide or alkoxide. 2. Process for the preparation of compounds of the formula in which R1 and R2 each represent aryl or alkyl groups, characterized in that formaldehyde is combined with a compound of the formula in which R1 and R have the same meaning as in formula III, condensed in an inert reaction medium in the presence of a catalytic amount of a strongly basic quaternary ammonium hydroxide or alkoxide and the reaction product obtained is reduced in a manner known per se. 3. Process for the preparation of compounds of the general formula wherein R1 and R2 each represent aryl or. Alkyigruppen, characterized in that formaldehyde with a compound of the formula wherein R1 and R2 have the same meaning as in Formula IV, condensed in an inert reaction medium in the presence of a catalytic amount of a strongly basic quaternary ammonium hydroxide or alkoxide, the product obtained to produce a compound of the formula in which R1 and R2 have the same meaning as in formula IV, and this compound is then reacted with phosgene in an inert solvent or with a dialkyl or diaryl carbonate in the presence of an alkaline catalyst. 4. Process for the preparation of compounds of the general formula in which R1 and R2 each represent aryl or alkyl groups, characterized in that a compound of the formula wherein R1 and R2 have the same meaning as in formula IV, producing an i-amino-2,2-disubstituted propanol of the formula wherein R1 and R2 have the same meaning as in formula IV, reduced and then this compound with pants in an inert solution vi. ittel or is reacted with a dialkyl or diaryl carbonate in the presence of an alkaline catalyst. 5. The method according to claims 1-4, characterized in that R1 is a phenyl group, which is optionally replaced by one or more alkyl, alkoxy or halogen substituents, and R2 is an alkyl group having 1-8 carbon atoms which is optionally substituted by a tertiary amino or alkoxy group is. 6. The method according to claims 1-5, characterized in that R1 is a phenyl group and R2 is an alkyl group having 1-4 carbon atoms. 7. The method according to claims 1-6, characterized in that R2 is an ethyl group. 8. The method according to claims 1-3 and 5-7, characterized in, that the inert reaction medium is toluene or a lower alkanol. 9. The method according to claims 1-3 and 5-7, characterized in that that the strongly basic quaternary ammonium hydroxide or alkoxide N-Benzyvtrimethylammoniummethoxid or hydroxide or tetramethyl, tetraethyl or tetra-n-butyl ammonium hydroxide is. 10. The method according to claims 1-3 and 5-7, characterized in, that the inert reaction medium benzyl and the strongly basic quaternary ammonium hydroxide Is N-benzyltrimethylammonium methoxide. 11. Compounds of the general formula where R1 is an aryl group and R2 is an alkyl group. 12. Compounds of general formula I according to claim 11, characterized characterized in that R1 is a phenyl group which is optionally substituted by an or several Al?: yl, alkoxy or halogen substituents are substituted, and R2 is one. Is an alkyl group with 1-8 carbon atoms, optionally substituted by a tertiary Amino or alkoxy group is substituted. 1. Compounds of the formula I according to claim 11, characterized in that that R1 is a phenyl group and R2 is an alkyl group having 1-4 carbon atoms. 14. α-Hydroxymethyl-α-phenylbutyronitrile. 15. α-Hydroxymethyl-α-phenylpropionitrile. 16. α-Hydroxymethyl-α-phenyl-β-methylbutyronitrile. 17. α-Hydroxymethyl-α- (p-methoxyphenyl) butyronitrile. 18. α-Hydroxymethyl-α- (m-chlorophenyl) butyronitrile. 19. Use of compounds of the general formula where R1 stands for an alkyl group and R2 for a phenyl group, as a new analgesic. 20. Use of compounds of the formula IV according to claim 19, characterized characterized in that R1 is a lower alkyl group and R2 is a phenyl group, the possibly by one or more hydroxyl, trifluoromethyl, halogen, lower Alkyl or lower alkoxy groups can be substituted. 21. Use of compounds of the formula IV according to claim 19, characterized characterized in that R1 is a lower il! yl group and R2 is a phenyl group. 22. Analgesic preparations containing the compounds of Claims 19-21 as an active ingredient.