SU454735A3 - Method for preparing carbamate ketoxime derivatives - Google Patents

Description

one

This invention relates to a process for the preparation of novel carbamate ketoxime derivatives with high biological activity.

 A method of obtaining carbamate is known.

I

derivatives of 2-akylthio (or hydroxy) alkane-a of oximes, the total 4 alkyl, alkenyl or alkynyl or --SRa -S (o) Rg, -. -oBg. -NRoRo. - K0 „. –CN З SSC. The mil of the Yak halogen and X can form a hereditary ring; terocyclic R, j - R hydrogen, lower alkyl, neither; shky alkenyl, lower quinil, substituted alkyl, alkenyl or quinil, while Rj; to R, may form a cycloaliphatic ring; R and R are hydrogen, lower alkyl, al6 kenyl or alkynyl; -S (o) Rg, X- -SRg -ORfl, -OS, -NRoRn, -NO. -NRgR, N. -CN. - scN or halogen;

- hydrogen, lower alkyl, lower

8 alkenyl or lower alkynyl, aryl, substituted aryl, carbamyl, substituted carba. mil, or aryl or substituted aiyl, such that lower alkyl or alkenyl radicals may be substituted by X; f l - hydrogen, or lower alkyl, while Rg, Rg and N in the group -NKgRg can form a heterocyclic ring ,. / get the interaction of the compound; general formula where R is R 5 and X have the indicated meanings, with an isocyanate of the general formula, Re ICO (III) has the indicated meaning. Among the compounds of general formula P obtained, carbamate derivatives possessing the highest biological activity, namely, 1-alkyl (alkenyl) thio (or G-azido) -2-alkanone oxime derivatives, in which carbamate nitrogen can be substituted with 0.1 or two, should be noted. lower alkyl groups; The carbon atom (C), the substituted alkylthio (or azido) group is not further substituted, the carbon atom is replaced by an alkyl group and full alkylation is optimal to ensure the maximum degree of branching of the carbon atom. The second preferred group of compounds of this formula are the carbamate derivatives of 1-vaql (alkenyl) thio (or I-azido) -2-alkanone oximes, in which the carbamate nitrogen may be substituted by OD, or by two lower alkyl groups; a carbon atom (C), a substituted alkyl (alkenyl) thio (or azido) group, is not further substituted; The carbon atom (Cn) is preferably substituted by group X and optimally fully 1-alkylated to provide the maximum degree of branching at the carbon atom. The method of producing these compounds consists in the interaction of the isocyanate with the oxime according to the following scheme: value. The oxime and isocyanate interact in an inert organic solvent at 0-150 ° C, preferably 2 ° -8 ° C, at a pressure of 1-10 atm, preferably 13 atm. The pressure at which the reaction is carried out depends on the reaction temperature, concentration and vapor pressure of the isocyanate. Whatever inert organic solvent is used to carry out the reaction, it should not contain hydro-: xyl groups, amino groups, and generally groups that can react with iso-shanata groups. Inert solvents are useful, for example, aliphatic and aromatic hydrocarbons (hexane, 1-heptane, octane, benzene, toluene, xylene); ethers (diethyl, dipropyl, ethyl propyl, esters, such as ethyl acetate, ethyl propionate); ketones (methylethylene ketone, acetone) and chlorine-containing hydrocarbons (methylene chloride, erchlorethylene), etc. The reaction is carried out preferably in the presence of 0.1-1 wt. %, based on the weight of the reactants, the catalyst is a tertiary amine (for example, triethylamine, N, N-dimethylaniline). The molar ratio of isocyanate to oxime can vary from 0.1: 1 to 1 O: 1. Preferably, an equimolecular ratio or a slight excess of the isocyanate is used with respect to the oxime. The reaction time is very different and ranges from several minutes to several days. Usually, it takes from 30 minutes to 6 hours to carry out the reaction. Example 1. 3,3-Dimethyl-2-methyl carbamyximino-1-tert-butylthiobutane. A solution of 4.7 g (0, O23 mol) of 3,3-dimethyl-1-tert-butylthio-2-butanoneoxin, 1.4 g (O, O25 mol) of methyl isocyanate and 3 drops of triethylamine in 35 ml of anhydrous ether is heated to boiling and K1sh t t with reflux for 16.5 hours. After evaporation of the volatiles on a rotary evaporator, the desired solid white product is obtained. T, pl. 105-1 ° 6 ° Calculated,%: C 55.3; H 9.3. Found,%: C 55.1; H 9.3. "Example 2. 2,2-Dimethyl-3-methyl-carbamyloximino-4-methylthiopentane. To a solution of sodium thiomethoxide, prepared from 4.1 g (0.18 g atom of sodium), 8.7 g (0.21 mol) of methanethiol, and HO ml of ethanol I, was added 34.5 g (0.18 mol) 4-bromo-2,2-dimethyl-3-pentanone for: 25 minutes at 0 + 5 ° С. After heating at 4 ° -45 ° C for 30 minutes, grow; the thief is filtered, the solvent is evaporated; dispersed to obtain 12 g of a colored: liquid with a so-called KIP. 57 ° C / 4.3 mmHg v .; P 1.4589. Calculated,%: C 59.9; H 10.1. : Found,%: C 59.2; H 10.1. 1.7 g (0.044 mol) of this compound and 18 g (0.26 mol) of hydroxylamine hydrochloride in 15O ml of absolute ethanol Containing 30 ml of pyridine, heated to boiling and refluxed with NIKOM for 12O hours. Pour the solution into ice water. The obtained solid with so pl. 128-129 ° C. Is 2,2-dimethyl-4-methylthio-3-pentanoxime Calculated: C 54.8; H 9.8; N 8. Found,%: C 54.8; H 9.4; N 7. A solution of 4.6 g (0.026 mol) of this oxime, 1.7 g (0.029 mol) of methyl isocyanate and 3 drops of ethylamine in 6 O ml. benzene is heated to boiling 1 G boil of t under reflux for 17 h. Having distilled off the volatiles, 6.2 g of a solid residue with m.p. 93-94 ° C, which is the desired product. Calculated,%: C 51.7; H 8.7; N12, Found,%: C 51.6; H 8.5; N 12.1. 60 Example 3. 4,4-Dictil-3-methylcarbamyl oxime and 1-m ethylthiopenta n. A solution of sodium thiomethoxide obtained by CP is 5.8 g (0.25 g atom), sodium, 13.5 g (0.28 mol) of methanethiol, 170 ml of absolute ethanol, is treated with 36.6 g (0.25 mol) of 1-chloro -4,4-dimethyl-3-pentanone at a temperature of from -3 to + 8 ° C for 30 minutes. After heating at 4 ° -45 ° C for 45 minutes, the mixture is filtered and dispersed, yielding 12 g of colored liquid with m.p. 73 C / 2 mmHg v .; 24 - - .. P 1.4623. Calculated,%: C 59.9; H 1O, 1. CgHjgOS Found,%: C 60.1; H 10. A solution of 22.5 g (0.14 mol) of this ketone and 58.4 g (0.84 mol) of hydroxylamine hydrochloride in 525 ml of absolute ethanol and 105 ml of pyridine is heated at the boil under reflux for 48 hours. Pouring the mixture into ice water gives 17.8 g of a white solid with m.p. which is 4,4-dimethyl-1-methylthio-3-pentanone oxime. Calculated,%: N 8. Found,%: N 8,1. A solution of 5.3 g (0.03 mol) of this oxime, 1.9 g (0.033 mol) of methyl isosinated, 3 drops of triethylamine in 5 O ml of anhydrous ether is refluxed and 1.6 g of a volatile are removed after the removal of 1 X volatile with t. pl. 56-58 ° C, which is the target product. Calculated,%: C 51.7; H 8.7; N12.1. Found,%: C 51.6; H 8.5; N 12.5. Example 4. 1-Cyclohexyl-1-methylcarbyloxymino-2-methylthioethane-. To a solution of 10.8 g (0.47 mol) of sodium in SZO ml of absolute ethanol was added L5POT 25 g (0.52 mol) of methanethiol, and then 76 g (0.47 mol) of chloroacetate. The reagents are introduced at about 0 ° C. After heating for one hour at 40-45 ° C, the reaction mixture is filtered, stripped, dispersed to obtain 29.8 g of a colored liquid with m.p. 88-89 ° C / 24 1.4970. / 0.6-1.3 mm Hg. v .; Calculated,%: C 62.7; H 9.4. Found,%: C 63.0; H 8.6. A solution of 26 g (0.15 mol) of 1-methylthioacetylcyclohexane, 21 g (0.3 mol) of hydroxylamine hydrochloride and 16 g (0.15 mol) of anhydrous sodium carbonate in 155 ml of 95% ethanol and 1 O4 ml of water is heated at reflux for 41 hours. Evaporation of the volatiles gives 18.0 g of a solid residue with m.n. 63-64 ° C. Calculated,%: C 57.7; H 9.2; N7.5. Found,%: C 57.5; H 9, O; N 7.4. A solution of 5.6 g (0.03 mol) of this oxime, 1.9 g (0.033 mol) of methyl ° isopianate and 3 drops of triethylamine in 50 m of absolute ether is heated at reflux for 17 hours. After removing the volatiles, 7.3 g of a solid are obtained, which, after recrystallizing from ethanol-water, gives a white substance with m.p. 70-71 ° C, is the desired product. Calculated,%: C 54.1; H 8.3; N11.5 Found: C 54.2; H 8.3; N 11.7. Example 5. 1-Methylcarbamyloximino-1- (1-methylcyclohexyl) -2-methylthioethane. 1 (Methylthioacetyl) -1-methylsh1Klogeksan is obtained by treating a solution of sodium thiomethoxide from 3 g (0.13 g-atom) sodium, 6.7 g (0.14 mol) of methanethiol, 95 ml of absolute ethanol, 22.5 g (0 , 13 mole) of 1-chloroacetyl-1-methylcyclohexane at 49 ° C for 2 minutes. After heating for one hour at 40-45 ° C, the reaction mixture is filtered and dispersed, yielding 7 g of colored liquid, m.p. 86-87 ° C / 0.8 mmHg v .; rtft 1,4954. Calculated,%: C L4.5; H 9.7. 10 "18 S Found,%: C 64; H 9.6. The ketone is converted to oxime by heating a solution of 5 g (O, O27 mol) of ketone, 3.8 g (0, O54 mol) hydroxylamine: hydrochloride and 3 g (O, O27 mol) of anhydrous sodium carbonate in 30 ml of 95% ethanol and 26 ml of water for 95 hours. The resulting solution is devolatilized to form a two-layer liquid residue, which is extracted with ethyl acetate. The organic layer is dried, filtered, and otparivat, getting 3.4 g of the smelling liquid; 1.5164. 8 Calculated,%: C 59.7; H 9.5; N 7. C. Found,%: C 59.8; H 9.5; N 7. A solution of 2.2 g (0.011 mol) of this oxime, 0.7 g (O, O12 mol) of methyl isocyanate and 3 drops of triethylamine in 25 ml of anhydrous ether is boiled under reflux for 16 hours. Stripping volatiles gives 3.5 g of a viscous, smelling liquid, which is the desired product; p 1,5200. About Calculated,%: C 55,8; H 8.6. Found,%: C 55.7; H 8.6. Example 6. 1- (1-Adamontil) -1-methylcarbamyloximino-2-metsh1Tioethane. i A solution of 4 g (0.036 mol) of 1-methylthio-acetyl admantane, 2.5 g (O, O36 mol) of hydroxylamine hydrochloride and 1.9 g (0.018 mol) of anhydrous sodium carbonate in 2 O ml of 95% ethanol and 18 ml of water are heated at reflux for 29 hours. By evaporation of the volatiles, a paste is obtained, after filtration of which 4.2 g of a white solid oxime with m.p. 10 O-103 C. Calculated,%: C 65.2; H 8.8; N 5.9. Found,%: C 65.5; H 8.8; N 5.6. Solution 3, O g (O, O 13 mol) of oxime, 0.8 g (O, 014 mol) of methyl isocyanate and 3 drops of triethylamine in 5 O ml of anhydrous ether are heated at reflux for 17 h. By evaporation, the volatiles obtained 3.9 g of a white solid with m.p. 89-90 C. Calculated,%: C 6O, 8; H 8.2; N 9.5. Found,%: C 60.2; H 8.1; N 9.5. Example 7. 1-Hpor-4,4-dimethyl-2-methylcarbamyloxyminopentane. To chilled sweetener dil. 21.5 g (0.145 mol) of 1-chloro-4,4-dimethyl-2-pentanol and 30 ml of 95% ethanol are added to a thief of 20.2 g (0.29 mol) of hydroxylamine hydrochloride in 10 ml of water. The cooled mixture is re-mastered for 6 hours, left to stand overnight, and then the volatiles are stripped to obtain a residue, which is extracted with ethyl acetate. The extract is concentrated, evaporated and distilled to give a colored liquid with m.p. 76-77 ° C / 1.3 mmHg v .; D 1, 4672.