DE1145631B - Process for the preparation of substituted 3-methylcarbaminotetrahydrofurans - Google Patents

Description

Process for the production of substituted 3-methylcarbaminotetrahydrofurans The invention relates to a process for the production of substituted 3-methylcarbaminotetrahydrofurans of the general formula in which R denotes an alkyl group with 1 to 6 carbon atoms, an alkynyl group with 2 to 6 carbon atoms or the phenyl group, R, and # R2 denotes lower alkyl groups with 1 to 6 carbon atoms, R denotes a hydrogen atom and X and / or Y denotes a hydrogen atom, straight - Or branched chain alkyl or alkylene radicals with 1 to 6 carbon atoms, which is characterized in that a disubstituted malonic acid diethyl ester of the general formula reduced in a manner known per se to the corresponding diol, the diol obtained is cyclized by treatment with mineral acids to give the corresponding 3-methylol tetrahydrofuran and this is cyclized in a manner known per se by treatment with phosgene and ammonia or ammonium hydroxide or amines of the general formula in which X and Y have the meaning given above, with the exception that X and Y cannot simultaneously represent a hydrogen atom, to the corresponding 3-methylcarbaminotetrahydrofuran.

The process according to the invention proceeds according to the following reaction scheme: It is not necessary to isolate or purify the intermediate products formed in the individual process stages.

The reduction of the disubstituted diethyl malonate is advantageously carried out with lithium aluminum hydride in the presence of an organic solvent, the diethyl malonate being added dropwise to the reducing agent with stirring and cooling. The reduction can be carried out at temperatures from -IO'C to the reflux temperature of the reaction mixture. 1.5 to 2 moles of lithium aluminum hydride are used per mole of diethyl malonate. The amount of the organic solvent can be varied within wide limits, but it is advisable to use so much solvent that a smooth reaction is possible. Suitable solvents are e.g. B. diethyl ether, higher molecular ethers and tetrahydrofuran. The excess lithium aluminum hydride and the reaction product obtained are decomposed by adding ice or moist ether, ethyl acetate or methanol. The majority of the precipitated solids can be dissolved and removed by acidification, and / or the reaction mixture can be extracted with ethyl ether, the latter procedure generally giving lower diol yields.

The reduction of the two ester groups can also be carried out according to other customary methods Methods, e.g. B. by means of sodium and alcohol.

For the cyclization of the diol obtained in the first stage, mineral acids such. B. hydrochloric acid or sulfuric acid is used. The cyclization can be carried out in such a way that a solution consisting of the diol in tetrahydrofuran, several hours with a small amount of a concentrated mineral acid, for. B. hydrochloric acid, is refluxed, or you can carefully add a small amount of concentrated hydrochloric acid to the diol and carry out the reaction at a temperature of less than 100'C. If an excess of mineral acid is used, the reaction temperature rises rapidly above 100.degree. C., as a result of which the yield of cyclized product is reduced. Those diols in which R 1 represents a methyl group and R 2 represents a hydrogen atom are particularly easily accessible to ring closure. These diols require very mild conditions in order to obtain good yields of the corresponding 3-methylol tetrahydrofuran.

To convert the 3-methylol tetrahydrofurans obtained in the second stage into the corresponding 3-Methylearbaminotetrahydrofurans z. B. the dissolved in tetrahydrofuran product to a concentrated solution of phosgene in tetrahydrofuran, expediently a temperature of -10 to -5'C is maintained. The reaction mixture containing the corresponding monochloro carbonate formed as an intermediate is then advantageously added to concentrated ammonium hydroxide, or gaseous amnionia can be introduced into the chlorocarbonate solution with cooling or the chlorocarbonate solution can be reacted with a corresponding primary or secondary amine.

The carbamates produced according to the invention show ataxic and paralytic effects on mice when administered intraperitoneally or orally. The pharmacological effectiveness of some process products is summarized in the table in which the dosages are given in milligra-mm per kilogram of body weight. Tabel R. R, IK CHPCONH2 > 1 - # O-- 1 R2CH, DLf ,. Mouse Pa Y's'er "de R R # IZ. Dose mouse intra- oral intra-oral peritoneal peritoneal # C, H, CH, H 585 660 300 450 CH, CH, H 840 2280 560 - C2H "CH, H 720 1400 260 470 C3H7 CH, H 600 2200 230 - C, H, CH3 H 420 - 188 - C, H5 CH, H 1140 - 770 - The 3-methylcarbamino-3-allyl-5,5-dimethyl-tetrahydrofuran and the 3-methylcarbamino-3,5,5-trimethyl-tetrahydrofuran showed marked anti-convalescent effects in mice that had jerks caused by the electric shock.

With the 3-methylcarbamino-3-allyl-5,5-dimethyl tetrahydrofuran in oral doses of 100 possible greater taming effects were achieved in monkeys than with the 2-methyl-2-n-propyl-1,3, which is used to determine the taming effects -propandiold-icarbamates at doses of 200 mg / kg. Similarly, the 3-methylearbamino-3-allyl-5,5-dimethyl-tetrahydrofuran caused sedation in dogs at a dose of 50 mg / kg, while in cats a dose of 100 mg / kg caused sedation, taming and muscle weakening . In clinical trials, the 3-Methylcarbamino-3-allyl-5,5 # dibli # reduced - 'thyl-tetrahydrofuran at a four times' the oral dose of 200 mg / day, anxiety and mood vagaries of patient to a greater extent than the known and used for the same purpose perphenazine. In addition, the process product was found to be free from undesirable side effects.

The following examples illustrate the process according to the invention: Example 1 3-Methylcarbainino-3-allyl-5,5-thinethyltetrahydrofuran A solution of 200 cc of anhydrous ethyl ether and 110.2 g of 2-allyl-2- (2'-methyl-propenyl) malonic acid diethyl ester ( Bp. 118 to 128'C) was added dropwise with stirring within 31/2 hours to a suspension of 33.0 g of lithium aluminum hydride and 450 ccm. Of anhydrous ethyl ether , the temperature of the reaction mixture increasing to -10 to -5'C The mixture was then stirred at this temperature for 1 hour and left to stand overnight at room temperature. The mixture was then cooled in an ice-salt bath. The excess lithium aluminum hydride and the organometallic complex formed by adding ice and water and the mixture is decomposed with as much 6 N hydrochloric acid treated so that it reacted weakly acidic, the mixture was then saturated with sodium chloride and extracted several times with ethyl ether.. the Unite th ethyl ether extracts were washed with water until they reacted neutral to Lakmus, and then the ether was distilled off, 72.2 g of crude 2-allyl-2- (2'-methylpropenyl) propanediol (1,3) as the residue yellow liquid remained. The diol obtained was dissolved in 50 cc of tetrahydrofuran, the solution was treated with 2 cc of concentrated hydrochloric acid, refluxed for 2 hours and the mixture obtained was distilled in vacuo. There were 57.6 g of 3-methylol-3-allyl-5,5-dimethyltetrahydrofuran-obtained as a colorless liquid of Kp.o, o5 bi, 0 ") 7 66 to 72'c. The yield was 78 0/0 theory .

34.0 g of the obtained 3-methylol-3-allyl-5,5-dimethyl-tetrahydrofuran was dissolved in 45 cc of tetrahydrofuran, and this solution was added in one hour at -10 to -5'C to a stirring at -10 until O'C solution of 39.6 g of phosgene in 40 cc of tetrahydrofuran was added dropwise. The mixture was stirred for a further hour and then added in the course of 21/2 hours at -10 to 15 ° C. to a mixture of 150 cc of concentrated ammonium hydroxide and 3.6 g of sodium bisulfite. The mixture obtained was stirred vigorously for a further ½ hours, the solid components were then dissolved by adding water, and the tetrahydrofuran was distilled off in vacuo. The remaining aqueous residue was left to stand in a refrigerator overnight. The 3-methylcarbamino-3-allyl-5,5-dimethyl-tetrahydrofuran crystallized out in the form of prisms with a temperature of 47 to 52 ° C. The yield was 20.9 g (77.1% of theory). Recrystallization of the crude product from methanol and water increased the melting point to 56 to 58 ° C. The overall yield was 60.20% of theory. Example 2 3-Methylcarbamino-3,5,5-trimethyltetrahydrofuran A solution of 250 ccm of anhydrous ethyl ether and 92.4 g of 2-methyl-2- (2'-methyl-propenyl) -malonic acid diethyl ester was stirred within 3 hours in a A nitrogen atmosphere was added dropwise to a suspension of 31 g of lithium aluminum hydride and 800 cc of anhydrous ether, the temperature being kept at O'C. The mixture was then stirred for 1 hour and allowed to stand at room temperature for 48 hours. Subsequently, the mixture in an ice-salt bath was cooled, decompose the excess lithium aluminum hydride, and the resulting organometallic complex by addition of ice, followed by addition of 300 cc of 6 N hydrochloric acid. The mixture was then treated with 125 cc of ethyl ether, the gummy mixture was saturated with sodium chloride and extracted five times with ethyl ether. The combined ether extracts were washed with water and the ethyl ether was distilled off. 44 g of 2-methyl-2- (2'-methyl-propenyl) -propanediol-1,3 were obtained as a yellow liquid as residue. The diol was then dissolved in 40 cc of tetrahydrofuran, 1 cc of concentrated hydrochloric acid was added to the solution and the mixture was refluxed for 2 hours. The resulting mixture was distilled in vacuo, 41.9 g (72 % of theory) of 3-methylol-3,5,5-trimethyl-tetrahydrofuran being obtained in the form of an oil with a boiling point of 92 to 105 ° C.

41.1 g of the 3-methylol-3,5,5-trimethyl-tetrahydrofuran obtained above were dissolved in 43 cc of tetrahydrofuran, and this solution became a solution prepared at -10 to OOC in 111 "hours at O'C with stirring of 50.2 g of phosgene in 23.1 cc of tetrahydrofuran was added dropwise.The mixture was then stirred for 2 hours, the temperature rising to 15 ° C. The resulting mixture then slowly became a mixture of 138 cc of concentrated ammonium hydroxide at 0 to 19 ° C and 4 g of sodium bisulfite were added, the solid fractions were dissolved by adding water, and the tetrahydrofuran was distilled off using a steam bath.The residue obtained was extracted several times with ethyl ether, the combined ether extracts were washed with water, dried, and the ether was distilled off. 50.1 g of a viscous liquid were obtained which crystallized on prolonged standing. The crystalline product was distilled in vacuo and gave 44.9 g (84.1 ") of the theory e) 3-methylcarbamino-3,5,5-trimethyl-tetrahydrofuran in the form of a viscous oil of bp "" 115 to 120'C, which slowly crystallized. After recrystallization from acetone-petroleum ether, the compound (35 g) melted at 46.5 to 47.5 ° C. The overall yield was 60.60% of theory. Example 3 3-Methylearbamino-3-propyl-5,5-dimethyltetrahydrofuran A solution of 100ccm of anhydrous ethyl ether and 102.4g of 2-propyl-2- (2'-methyl-propenyl) -malonic acid diethyl ester (bp "140 to 145'C ) was slowly added with stirring over a period of 2 to 3 hours to a suspension of 30.4 g of lithium aluminum hydride in 450 cc of ethyl ether, the temperature being kept at 10 to 20 ° C. The mixture was then stirred in a cooling bath for 1 hour and then The excess lithium aluminum hydride and the organometallic complex formed were then decomposed by adding ice and then adding 120 cem of 6N hydrochloric acid.The product was then isolated by the method described in Example 1. 68.4 g were obtained crude 2-propyl-2- (2'-methyl-propenyl) -propanediol-1,3. the diol obtained was cooked with 2cc of concentrated hydrochloric acid in 80 cc tetrahydrofuran reflux for 2 hours. concentration of the reaction Mixture and subsequent distillation in vacuo gave 58.6 g (85.2 "/, of theory) of 3-methylol-3-propyl-5,5-thinethyl-tetrahydrofuran with a boiling point of 74 to 94 ° C.

27.1 g of the above obtained 3-methylol-3-propyl-5,5-dimethyl-tetrahydrofuran were dissolved in 50 cc of tetrahydrofuran, and this solution was in% hours under stirring to a solution of 50 cc of tetrahydrofuran and 31.2 g of Phosgene was added dropwise, the temperature being kept at -10 to O'C. The mixture was left to stand for 1 hour at room temperature and then added at 0 to 10 ° C. to a large excess of concentrated ammonium hydroxide. The mixture obtained was stirred for 1/1 hour, then about 100 cc of water were added and the tetrahydrofuran was distilled off. The residue was extracted with ether and the ether was distilled off. The residue was destilhert, whereby 14.7 g (44.1 ", the theory /) 3-Methylcarbamino-3-propyl-5,5-dimethyl-tetrahydrofuranvom Kp.0,07 to obtain o.12 105 to 140'C The total yield was 37.6% of theory. Example 4 3-Methylcarbaniino-3-propargyl-5,5-dimethyltetrahydrofuran A solution of 200 cc of ethyl ether and 73.3 g of 2 - propargyl - 2 - (2'- methyl - propenyl) -. diethyl malonate was added slowly to a suspension of 22.1 g of lithium aluminum hydride and 400 cc of ethyl ether over 3 hours while the temperature was maintained at -5 to + 5 ° C. the mixture was then stirred at this temperature for 3 hours The excess lithium aluminum hydride and the organometallic complex formed were then decomposed by adding ice and water to the mixture, and the mixture was treated with 125 cc of dilute hydrochloric acid (1: 1) so that it reacted slightly acidic Product was then processed according to the im Example 1 described method isolated. 41.1 g (84.8 "/, of theory) of crude 2-propargyl-2- (2'-methyl-propenyl) -propanediol-1,3 of bp", o, to "" 50 to 97 'were obtained C. 15.6 g of the crude diol obtained were dissolved in 45 cc of tetrahydrofuran containing 0.5 cc of concentrated hydrochloric acid and refluxed for 11½ hours, and the resulting mixture was distilled in vacuo. (Theory 80.8 0 /,) 3-methylol-3-propargyl-5,5-dimethyl-tetrahydrofuran, bp-10 to give 12.6 g to 5 92 to -124'C. The 3-methylol-3-propargyl-5,5-dimethyl-tetrahydrofuran obtained was then treated according to Example 1 with a solution prepared at -10 to O'C from 11.1 g of phosgene and 65 cem of tetrahydrofuran and 55.5 cc of ammonium hydroxide , whereby 10.5 g (66.501, of theory) 3-methylcarbamino-3-propargyl-5,5-dimethyl-tetrahydrofuran of bp "2 to 0.4 96 to 122 ° C. were obtained. The total yield was 45.6 0 /, of the theoretical. example 5 3-Methylcarbamino-3-ethyl-5,5-dimethyltetrahydrofuran A solution of 2040 cc of ethyl ether and 254.7 g of 2-ethyl-2- (2'-methyl-propenyl) was -malonsäurediäthylester by using 60 g of lithium aluminum hydride using the method described in Example 6. 124.6 g (74.3 % of theory) of 2-ethyl-2- (2'-methyl-propenyl) -propanediol-1,3 from KP were reduced -15 to 2o 140 to 147 ° C., with 950 /, distilled at 146 to 147 ° C. The diol obtained was dissolved in tetrahydrofuran to which 2 cc of 12N hydrochloric acid had been added, the mixture for 2 hours under reflux Boiled under water and then distilled in vacuo. 119.4 g (95.8 l) /, of theory) of 3-methylol-3-ethyl-5,5-dimethyl-tetrahydrofuran VOM KP-ir, to 20 118 to 124 ° C. were obtained. 53 g of the 3-methylol-3-ethyl-5,5-dimethyl-tetrahydrofuran obtained were treated, as described in Example 1 , with 55 g of phosgene and 180 cem of ammonium hydroxide, 59.1 g (87.70 / 0 theory) crude 3-methylcarbamino-3-ethyl-5,5-dimethyl-tetrahydrofuran were obtained. Recrystallization from methanol and water gave 33.9 g of pure 3-methylcarbamino-3-ethyl-5,5-dimethyl-tetrahydrofuran with a melting point of 53.5 to 55.0 ° C. The overall yield was 62.40/0 of theory. Example 6 3-Methylearbamino-3-phenyl-5,5-dimethyltetrahydrofuran A solution of 138 cc of ethyl ether and 69 l'e 2-P, henyl-2- (2'-methyl-propenyl) -malonic acid diethyl ester was within 21 /, Hours added to a suspension of 14.1 g of lithium aluminum hydride, and 365 cem of dry ethyl ether, the temperature was kept at -5 to 10'C. The mixture was then stirred at room temperature for 2 hours and left to stand overnight. The excess lithium aluminum hydride and the resulting organometallic complex were then decomposed by adding methane or methanol and water and finally water. The solid fractions obtained in this way were separated off and washed several times with ethyl ether. All ether components were combined, washed with water, dried, and the solvent was distilled off, whereby 45.5 g (92.7 % of theory) crude 2-phonyl-2- (2'-methyl-propenyl) -propanediol -1,3 obtained roots. The crude diol obtained was dissolved in 40 cc of tetrahydrofuran, 1 cc of concentrated hydrochloric acid was added to the solution and the mixture was boiled under the reflux for 2 hours. 45.3 g (99.5% of theory) of crude 3-methylol-3-phenyl-5,5-dimethyl-tetrahydrofuran were obtained. The distillation of the crude product gave a fraction of 19.4 g of 3-methylol-3-phenyl-5,5-dimethyltetrahydrofuran with a boiling point of 90 to 140 ° C., the majority of which passes over at 120 ° C. -Methylol -3- phenyl - 5,5 - thinethyl- tetrahydrofuran (19.4 g) was dissolved in 26 cc of tetrahydrofuran, and this solution became a solution of 13.98 g in one hour at -10 to + 2 ° C Phosgene and 50 cc. Of tetrahydrofuran were added dropwise. The solution was then stirred for 1/2 hour in an ice bath and left to stand for several hours at room temperature. Subsequently, the resulting mixture became a mixture of 90 cc. Of concentrated ammonium hydroxide and 0.5 g of sodium bisulfite added dropwise, the temperature being kept at 0 to 20 ° C. The tetrahydrofuran was distilled off and the residue was extracted with ethyl ether. The ether extract was washed with water and the ether was distilled off. The residue obtained was 18.6 g (80.00 /, the theory) crude 3-methylcarbaniino-3-phe nyl-5,5-dimethyl-tetrahydrofuran. After recrystallization from methanol and water, the compound melted at 81 to 84 ° C. The overall yield was 73.8% of theory. Example 7 3-Methyl-N-isopropyl-earbamino-3-allyl-5,5-thinethyl-tetrahydrofuran As described in Example 1 , starting from 110.2 g of 2-allyl-2- (2-methyl-propenyl) -malonic acid diethyl ester, the 3-methylol-3-aHyl-5,5-thinethyl-tetrahydrofuran produced. 12 g of the 3-methylol, -3-allyl-5,5-dimethyl-tetrahydrofuran obtained were dissolved in 25 cc of tetrahydrofuran, and this solution was added dropwise in 30 minutes to a solution of 50 cc of tetrahydrofuran and 6.6 g of phosgene, whereby the temperature was kept below 5'C. The mixture was then stirred in an ice bath for 30 minutes. A stream of nitrogen was then passed through the solution in order to remove the excess phosgene. The chlorocarbonate solution obtained was then added dropwise over the course of 75 minutes to a cooled solution of 12.8 g isopropylamine and 150 cc of tetrahydrofuran, the temperature being kept below 5 ° C. The resulting mixture was then stirred at room temperature for 1 hour, the salts were dissolved by adding water, and the tetrahydrofuran was distilled off. The residue obtained was diluted with a solution of 6 g of sodium hydroxide and 12 cc of water, the mixture was saturated with sodium chloride and extracted with ethyl ether. The ethyl ether was then distilled off, and 14.9 g of crude 3-methyl-N-isopropyl - carbamino-3- allyl -5,5- dimethyl - tetrahydrofuran were obtained. By distilling this residue, 11.5 g of 3-methyl-N-isopropyl-carbamino-3-allyl-5,5-dimethyl-tetrahydrofuran of KP "w bi""" 88 to 100 ° C. were obtained. The yield was 63.9% of theory. The total yield was 49.9 "/, of theory. Example 8 3-Methyl-N, N-diethyl-carbamino-3-allyl-5,5-dimethyl-tetrahydrofuran As described in Example 1 , starting from 110, 2g 2-allyl-2- (2'-methyl-propenyl) -malonsäurediäthylester, 3-methylol-3-allyl-5,5-dimethyltetrahydrofuran prepared. 17 g of the obtained 3-methylol-3-allyl-5,5- dimethyl-tetrahydrofurans were dissolved in 30 cc of tetrahydrofuran, and this solution was added dropwise to a solution of 50 cc of tetrahydrofuran and 14.85 g of phosgene over the course of one hour, the temperature being kept at -5 to + 5 ° C. The solution was then The resulting solution of the crude chlorocarbonate was then added over the course of 2 hours to a solution of 50 g of diethylamine and 100 cc of tetrahydrofuran, the temperature being kept at -5 ° C. The precipitated solid components were then added dissolved in 75 cc of water, and the solvent was distilled off; the aqueous residue obtained was extracted with ethyl ether and the ether extract was separated off. After distilling off the ether, 32.2 g of a crude residue were obtained, from which 17.65 g (65.5 "/,) of 3-methyl-N, N-diethyl-carbamino-3-allyl-5 , 5-dimethyl-tetrahydrofuran of bp O ", bi,""80 to 900C. The overall yield was 51.20% of theory.

Claims (1)

PATENT CLAIM: Process for the preparation of substituted 3-methylcarbaminotetrahydrofurans of the general formula in which R is an alkyl radical with 1 to 6 carbon atoms, an alkylene radical with 2 to 6 carbon atoms, an alkynyl radical with 2 to 6 carbon atoms or the phenyl radical, R, and R2 is lower alkyl radicals with 1 to 6 carbon atoms or R2 is a hydrogen atom and X and / or Y represents a hydrogen atom, straight or branched chain alkyl or alkylene radicals with 1 to 6 carbon atoms, characterized in that a disubstituted malonic acid diethyl ester of the general formula reduced in a manner known per se to the corresponding diol, the diol obtained is cyclized by treatment with mineral acids to give the corresponding 3-methylol tetrahydrofuran and this is cyclized in a manner known per se by treatment with phosgene and ammonia or ammonium hydroxide or amines of the general formula in which X and Y have the meaning given above, with the exception that X and Y cannot simultaneously represent a hydrogen atom, to the corresponding 3-methylcarbaminotetrahydrofuran. Considered publications: Houben-Weyl, Methods of Organic Chemistry, 4th Edition, Vol. VIII (1952), pp. 101/102, 1J8 (Section a) and 643 to 645, Dunlop-Peters, The Furans (1953 ), Pp. 21 to 23.