Process for preparing derivatives of heterocyclic phenoxyamines

专利摘要:
A method for producing hetero-cyclic phenoxyamines of the general formula O with p 2, p O with m 2, or their optically active isomers or their salts, characterized in that the sodium phenol of the general formula is ONa where A and X have the indicated meanings, is reacted with a compound of the general formula. -O Y- CH. And R has the indicated values where I is a halogen and the target product is isolated in free form or in the form de salts, or divided into optical isomers. Priority on the basis of: 06.07.79 with A - hydrogen, methoxy or ethoxy, X - chlorine or bromine, K - methyl, ethyl, allyl or cycloOO hexyl. - methoxy or ethoxyl; X - chlorine or bromine; R - cyclopropylmethyl.
公开号:SU1085507A3
申请号:SU802938255
申请日:1980-07-01
公开日:1984-04-07
发明作者:Томине Мишель；Франсешини Жаклин
申请人:Сосьете Д Этюд Сьянтифик Э Эндюстриель Де Л Иль-Де-Франс (Фирма)；
IPC主号:

专利说明:

This invention relates to a process for the preparation of new derivatives of heterocyclic phenoxyamines of the general formula (CHO), (10 - ((1H2) w-CHC, (where A is hydrogen, methoxy or ethoxyl) I. X is chlorine or bromine, R is methyl, ethyl, allyl, cyclohexyl, cyclopropylmethyl or cyclohexenylmethyl; m O with p 2; p O with m 2 y or their optically active isomers or their salts that have an effect on the central nervous system, in particular with a local anesthetic effect. reaction of the preparation of phenol ethers by the interaction of phenols of alkali compounds talles with alkyl halides ij. The aim of the invention is to obtain new derivatives of heterocyclic phenoxyamines of the general formula (1), based on the known reaction of alkali metal phenols with halide alkyls. The goal is achieved by the fact that according to the method of obtaining new derivatives of heterocyclic phenoxy-ins, total Formula (I), involving the interaction of a sodium fnol and the general formula. A (P where X and A have the indicated meanings with a compound of the general formula (w Y-dHj-CHf if where R has the indicated values, I is halogen. The reaction between compounds of formula (p) and compounds of formula (P) takes place in an inert organic solvent, for example, xylene or toluene, at the boiling point of the reaction mixture. The obtained compounds are separated and purified by limestone methods, for example, extraction, preparation of gels, by recrystallization, by chromatography. The separation of the compounds of general formula (1) is carried out using an optically active acid. Example 1. 1-Methyl-4- {2-meth hydroxy-3,5-dichlorophenoxy) hexamethylene min, 1-methyl-2- (2-methoxy-3, 5-dichlorophenoxyethyl) pyrrolidine. 13 g of sodium are dissolved in 180 ml of ethanol in a two-liter flask equipped with a pressure seal, a reflux condenser and a thermometer, and 108 g of 3.5-dichlorohydroacol (0.56 mol) and 300 ml of dry toluene are added to the solution. The reflux condenser is then replaced with a Vigro 40 cm column and the entire alcohol is removed by azeotropic distillation. After removal of the alcohol, the sodium salt of 3,3-dichlorohydric crystallizes into a dense mass. At the end of the distillation stage, toluene is added, which is equal in volume to the removed toluene, and then cooling is carried out. The Vigrau column was again replaced with a reflux condenser and 103 g of 1-methyl-2- (2-chloroethyl) pyrrolidine (0.56 mol + 25% excess) was added. The resulting mixture is slowly brought to the boiling point of the reaction medium. The mixture quickly dissolves when heated. After the reaction becomes less vigorous, the mixture is again heated to boiling point and maintained at this temperature for 8 hours. The reaction mixture is then cooled and dissolved in 400 ml of water and 80 ml of concentrated hydrochloric acid. The toluene is decanted and washed twice with acidified water. The aqueous solutions are combined, filtered using carbon black and alkalinized by adding a 20% ammonia solution until phenolphthalein changes color. The oil which separates in this way is decanted and extracted with ether. The ether solution is dissolved over potassium carbonate. The ether is distilled off, at the final stage under vacuum, until a constant weight is obtained. Received 182 g of the product. Using those (MERK 5554 silica, eluent - benzene: ethanol: ammonia- 84: 15: 1) it was established that the product obtained is a mixture of essentially equal parts of two isomers: 1-methyl-4- (2-methoxy-3 , 5-dichlorophenoxy) hexamethylenimine and 1-methyl-2- (2-methoxy-3, 5-dichlorophenoxyethyl) pyrrolidine. The base mixture is dissolved in 400 ml of methyl ethyl ketone and 20.5 g of dry hydrochloric acid (0.56 mol) is added in solution in 40 ml of methyl ethyl ketone. Begin crystallization. The solution is incubated overnight. The hydrochloride is isolated by filtration, washed with methyl ethyl ketone and dried at 40 ° C. Obtain 97 g of product with so pl. 155-157p. In accordance with TLC analysis, it was found that the main part of this hydrochloride contains a derivative of hexamethylenimine. Uterine solutions are subjected to the slightest treatment in order to obtain the pyrrolidine PREEID. The hydrochloride is recrystallized twice in 185 and acetonitrile, respectively. 69.5 g of 1-methyl-4- (2-methoxy-3, 5-dichlorophenoxy) hexamethylenimine hydrochloride are obtained with mp 161-162.5 ° C. Yield 69.5 g (36.5%). The elemental analysis data of the obtained compound are given in Table 1. The stock solutions of hydrochloride are dissolved in a small amount of water and the methyl ethyl ketone is distilled off. The remaining solution is diluted with 325 ml of water, filtered using carbon black and alkalinized with a 20% ammonia solution until phenolphthalein changes color. The oil which is separated is decanted and extracted with ether. The ether solution is dried over potassium carbonate and then the ether is distilled off at the final stage using vacuum until a constant weight is obtained. The resulting weight is 82 g. Dissolve in 230 ml of hot isopropanol 82 g of base (0, 27 mol and 31.5 g of fumaric acid (0.27 mol is cooled and the precipitate formed is filtered. 109.5 g of fumarate is obtained. The resulting fumarate is recrystallized from 275 ml of methanol. 78 g of 1-methyl-2- (2-methoxy-3 is obtained , 5-dichloro phenoxyethyl) pyrrolidine fumara1 with a mp of 179-180 ° C. Yield 78 g (33%). Analysis by TLC detected a yield of the effect of a small amount of a hexamethylenimine derivative that was not detected using an NMR spectrum Example 2. Progravity of 1-methyl-2- (2-methoxy-3, 5-dichlorophenoxyethyl) pyrrolidine. The fumarate of a racemic product is converted into a base using aqueous ammonia and extracted with ether. 161 g of this base (0.53 mol) are dissolved in 320 ml of methanol and 199 g of L (+) dibenzoyl tartaric acid (0.53 mol) in 400 ml of methanol is added to a solution. The dibenzoyl tartrate immediately crystallizes. After overnight, the crystals are separated, washed with 300 ml of methanol and dried at 40 ° C. 161 g of product is obtained with a melting point of 160 ° C, Mie (5% solution of dimethylformamide). 157 g of dibenzoyl tartrate is dissolved in 200 ml of dimethylformamide, and then 65 ml of water is added to it, which gives an 80% solution of dimethylformamide. Upon cooling, the crystals, the salts are separated by filtration, washed with 200 ml of an 80% dimethylformamide solution and then with water, dried at 40 ° C. Get 136 g of the product with so pl.140-141s, -36.5 (5% solution of dimethylformamide). 136 g of dibenoyl tartrate, 600 ml of water, 45 ml of a 20% ammonia solution and 300 ml of ether are loaded into a three-liter flask equipped with a stirrer. The base which precipitates is immediately dissolved in ether and then decanted. The aqueous solution is extracted with ether and the resulting ethereal solution is dried over potassium carbonate, and then the ether is distilled off at the final stage under vacuum until a constant weight of 61.5 is obtained (1 47.5 (5% - dimethylformamide solution.) 61.5 g of base (0.202 mol) in the presence of 170 ml of water and 23.5 g of fumaric acid (0.202 mol) are heated to form a solution. The resulting boiling solution is filtered using carbon black. When cooled, the fumarate slowly crystallizes The crystals are separated by filtration, washed with water. th and dried at 40 ° C. Obtain 74 g of fumarate with T. p.157157, 5 C. Yield 74 g (34%), 5 (5% solution of dimethylformamide). Example 3. Levorotatory 1-methyl-2- ( 2-methoxn-3, 5-dichlorophenoxyethyl) pyrrolidine. Alcohol solutions obtained during the formation of the 1-methyl-2- (2-methoxy-3, 5-dichlorophenoxyethyl) pyrrolidine-dibenzoyl tartrate programer and containing about 88 g of base are concentrated and the residue is dissolved. in 400 ml of water, 60 ml of 20% ammonia solution and ether with vigorous stirring. The base which precipitates is dissolved in ether. The ether solution is decanted. The aqueous phase is extracted three times with ether. The ether phases are combined dried over potassium carbonate. The ether is distilled off at the final stage under vacuum until a constant weight is obtained. 69.5 g of base are obtained. 67 g of base (0.22 mol) is dissolved in 140 ml of methanol and then a solution of 8.3 g of - ((-) dibenzoyl tartaric acid (0.22 mol)) in 165 ml of methanol is added. Dibenzoyl tart eate crystallizes immediately. It is filtered, washed with methanol and dried at 40 ° C. Product weight: -i 126 G, m.p. 1 34-1 ,, - 437, 2 U-ni, (i grow dimethylformed dminda i. 124 g of dibenzoyl tartr la dissolve in the will and in excess (1 mmnac). The base, which is separated off, is quickly extracted with , the solution is decanted and the aqueous phase is extracted with a simple;) phase. The ether phases are combined and dried with potassium carbonate. The ether is then distilled off at a final stage under vacuum until constant weight of 56 g, 8 ° is obtained. 54 g of base (0.178 mol), 145 ml of water and 21 g of fumaric acid (0.178 mol) are charged into an LLC ml round bottom flask equipped with a reflux condenser. and the mixture is heated until a solution is obtained. The resulting boiling solution was filtered using carbon black. When cooled, fumarate crystal appears. It is separated by filtration, washed with water and dried at. Get 68 g of the product with so pl. 157-158 ° C, ot.j -17.8 ° (5% solution of dimethylformamide). Inlet 60.5% Example 4. 1-P1LLIL-4- (2-meth hydroxy-3,5-dichlorophenoxy) hexamethylene min, 1-allyl-2- (2-methoxy 3,5-dichloro-phenoxyethyl) pyrrolidine. Analogously to example 1, using 246 g of 3,5-dichlorohydric naphtha (1.275 mol) and 221 g of 1-allyl-2- (2chloroethyl) pyrrolidine (1.275 mol.), 411 g of a mixture of essentially equal parts of two isomers are obtained: 1-allyl-4 - (2-methoxy-3, 5-dichlorophenoxy hexamethylenimine and 1-allyl-2- (2methoxy-3, 5-dichlorophenoxyethyl) pyrrolidine. 397 g of a mixture of bases (1.20 mol) is dissolved in 1250 ml of acetonitrile and then added 230 g of dry citric acid (1.20 mol). The suspension is heated to form a solution, and then the solution is cooled over night. The precipitate is filtered off, washed with 1200 ml of acetonitrile, dried in air and then in a dry oven with.To obtain 538 g of a mixture of citrates of two products: OTU mixture is recrystallized three times after the mixture has been passed through carbon black in 95% alcohol. 227 g of product is obtained, the NMR spectrum shows the structure of hexamethylene mine, t mp 90-95 ° C. Yield 37%. Acetonitrile after washing and alcohol after recrystallization are distilled at a final stage under vacuum. The residue is dissolved in water and filtered using carbon black. Then the base is precipitated by adding a 20% solution until phenolphthalein changes its own. coloring. The oil, which we learn otdelchots, locate and ex-rilirut ether. The ether piiCTDOp cyuja-j is over potassium carbonate and the ether is distilled off at the final stage using vacuum until a constant weight is obtained. 184 g of base (0.56 mol) is formed, which is dissolved in the hot state in 550 ml of isopropanol and 65 g of fumaric acid (0.56 mol). Upon cooling, the fumerate is crystallized and separated by filtration, then washed with isopropanol, dried in air, and then at 40 ° C. 141 g of product are obtained with a mp of 135-136 ° C. 140 g of fumarate are recrystallized from 275 ml, and then from 145 ml of isopropanol and, finally, from 190 ml of water. 90 g of 1-allyl-2- (2methoxy-3, 5-dichlorophenoxyethyl) pyrrolidine-fumarate is formed with a melting point of 137-138 ° C. The yield is 16.5%. Example 5. 1-Ethyl-2 (3,5-dichlorophenoxyethyl) pyrroli. Dissolve 19 g of sodium in 245 ml of absolute alcohol in a two-liter flask equipped with a compactor, a reflux condenser and a thermometer. The ethylate solution is cooled and 133 g of dichlorophenol (0.815 mol) and 430 ml of dry toluene are added to it. The reflux condenser is replaced with a Vigro column and the alcohol is removed by azeotropic distillation. Sodium salt of dichlorophenol precipitates and the medium becomes thick, although it can be stirred. After cooling, the Vigrau column was replaced with a reflux condenser, 139 g of 1-ethyl-2- (3-chloroethyl) pyrrolidine (0.815 mol + 5% excess) was added to the mixture and the mixture was heated to boiling point, which was maintained for 1 h. -ethyl-2 - (- chloroethyl) pyrrolidine is obtained from its hydrochloride immediately before use. After the reaction is complete, the reaction mixture is dissolved in 1.8 l of water and 85 ml of concentrated hydrochloric acid. The toluene phase is decanted and then washed with 100 ml of water and 10 ml of concentrated hydrochloric acid. The aqueous phases are combined, filtered with carbon black and converted to alkaline by adding a 20% ammonia solution until the phenolphthalein changes its color. The oil, which is separated, is extracted with ether and the ether solution is dried over potassium carbonate. After removal of the ether, the product is distilled under vacuum. Intermediate fraction: 180-182 / / 5 mmHg Weight 175 g
175 g of base (0.61 mol) is dissolved in 335 ml of methyl ethyl ketone, and then a solution of 22.5 g of dry hydrochloric acid (0.61 mol) in 260 ml of methyl ethyl ketone is added to change the color of methyl red. The hydrochloride is slowly crystallized and separated by filtration, washed with 130 ml of methyl ethyl ketone and dried in a drying oven. 151.5 g of hydrochloride is formed.
Chromatographic analysis of this material (MERK 5554 silica-alumina benzene: ethanol: ammonia 84: 15: 1) showed that it is a mixture of 1-ethyl-2- (3,5-dichlorophenoxy-ethyl) pyrrolidine hydrochloride and 1-ethyl-4- (3,5-dichlorophenoxy) hexamethylenimine. The mixture has a higher content of pyrrolidine,
150 g of the hydrochloride mixture is recrystallized from 150 ml and then from 225 MP of acetonitrile. 46 g of product material are obtained. 138-140 ° C. It is then recrystallized from 95 ml, then from 50 ml of isopropanol, resulting in the formation of 27 g of product with mp 152153 ° C. As a result of chromatographic analysis, only one spot was obtained. Yield 10.5%.
Example 6. 1-Methyl-2- (2-methoxy-3, 5-dibromophenoxyethyl) pyrrolidine.
15 g of sodium are dissolved in 215 ml of absolute ethanol in a two-liter round-bottom flask equipped with a stirrer, a reflux condenser and a thermometer. 187 g of 2,5-dibromgvayacol (0.66 mol) in 365 ml of dry toluene is added. The alcohol is completely removed by azeotropic distillation. The result is a thick suspension, to which 190 ml of toluene is added. Cool and then 102.5 g of 1-methyl-2- (3-chloroethyl) pyrrolidine (0.66 mol + 5% excess) is added. The resulting mixture was kept at boiling point for 8 hours. The reaction mixture was then dissolved in 500 ml of water and 66 ml of hydrochloric acid (d 1.18) The toluene layer was decanted and washed with 200 ml of dilute (1:20) hydrochloric acid. The aqueous solutions are combined and filtered with carbon black and then alkaline with a 20% ammonia solution. The oil is decanted and extracted with ether.
The ether solution is dried with potassium carbonate and then the ether is distilled off until the weight is stabilized. 165 g of base are formed, which as established by TLC is a mixture of the following isomers: 1-methyl-4- (2-methoxy-3,5-dibromophenoxy) hexamethylenimine and 1-methyl-2 (2-methoxy-3, S - dibromophenoxy ethyl 1-pyrrolidine.
164 g of base (0.448 mol) was dissolved in ethanol and a solution of 52 g of fumaric acid (0.448 mol) in 685 ml of absolute alcohol was added to the resulting solution. Upon cooling, the fumarate is crystallized and then separated by filtration, washed with alcohol and dried. Using TLC analysis of this material, it was found that it contains more pyrrolidine derivative. The fumarate is purified by recrystallization from 320 ml of methanol, then recrystallization twice from 100 ml and 80 ml of dimethylformamide. respectively. 33 g of 1-methyl-2- (2-methoxy-3, 5-dibromophenoxyethyl) pyrrolidine fumarate with mp. 192 ° C. Yield 10%.
0
Example 7. 1-Ethyl-2- (2-methoxy-3, 5-dichlorophenoxyethyl) pyrrolidine.
Analogously to Example 1, the HPZZg gvayacol (1.72 mol) is reacted
5 and 292 g of 1-ethyl-2 - (/ E-chloroethyl) pyrrolidine (1.72 mol + 5% excess), which is prepared immediately before the reaction from its hydrochloride, resulting in the distillation
0 414 g of product is obtained which is distilled at 173-180 ° / 1 mm Hg. The resultingfemecTBO is dissolved in 800 ml of methyl ethyl ketone-. A solution of 47.5 g of dry hydrochloric acid in 400 ml of methyl ethyl acetate is added. The hydrochloride is crystallized on cooling and then separated by filtration, washed with methyl ethyl ketone and dried in a drying oven at 40 ° C. As a result, 306.5 g of chloro-hydrate are obtained with a mp of 126-128 ° C, which is recrystallized from 613 ml of acetone.
252 g of 1-ethyl-2- (2-methoxy-3, 5-dichlorophenoxyethyl) pyrroli5 din hydrochloride are obtained with a mp of 129.9-130 ° C., 41% yield.
Example 8. Prograviruet 1ethyl-2- (2-methoxy-3, 5-dichlorophenoxyethyl) pyrrolidine.
0
175 g of 1-ethyl-2- (2-methoxy-3, 5-dichlorophenoxyethyl) pyrrolidine (0.55 mol) is dissolved in 260 ml of 95% ethanol. A solution of 82.5 g of dextroar tartaric acid (0.55 mol) in 260 ml of 95% ethanol is added. After cooling and adding a seed crystal, the tartrate crystallizes. It is separated by filtration, washed with 100 ml of 95% ethanol and dried at 40 ° C. 104 g of the right deforming tartapaTa; t l +21.5 ° (5% aqueous solution) is formed.
I recrystallized 103.5 g of tartrate from 207 ml of 95% ethanol. 82 g of product are obtained, ti 24.3 (5% aqueous solution). 81 g of tartrate is dissolved in 425 ml of lukewarm water and then the base is precipitated by the addition of 20% ammonia solution. The oil which is decanted is extracted with ether. After drying the ether phase and evaporation, 47.5 g of base, ci +55, 8 (5% solution of dimethylformamide) are obtained. 46 g of base (0.145 mol) in 140 ml of ethyl acetate are dissolved, and a solution of 5.5 g of dry salt is added. Acidic acid (0.145 mol) in 55 ml of ethyladetate, the hydrochloride is crystallized, separated by filtration, washed with ethyl acetate and dried in a drying oven at 40 ° C. 47.5 g of the crude product is formed with mp, 121-122 ° C, ° (5% aqueous solution) Yield 25%, Example 9, Levorotatory 1-ethyl-2- (2-methoxy-3,5-dichlorophenoxyethyl) pyrrolidine. The alcoholic liquids that were formed during the precipitation and recrystallization of the protracted 1-ethyl-2 (2-methoxy-3,5-dichlorophenoxyethyl) pyrrolidine tartrate were dissolved in 850 ml of water and concentrated to 400 ml. A solution of 31 g of potassium chloride (0.375 mol + 10% excess) in 140 ml of water is added. The potassium tartrate that precipitates is separated by filtration and washed with water. The above liquid is alkalized using a 20% ammonia solution. The oil is decanted, extracted with ether and the ether solution is dried over potassium carbonate. The ether is then distilled off to complete the stage under vacuum until the weight is stabilized. 107 g of product is formed, which is a mixture of approximately 20% of the pro-rotational base and 80% of the levorotatory base. This product is dissolved in 160 ml of absolute ethanol and then 53 g of levorotatory tartaric acid dissolved in a hot state in 160 ml of ethanol are added. The solution is filtered and then cooled. The tartrate is crystallized, separated by filtration, washed with 95% ethanol and dried in a drying oven at 40 ° C. 107.5 r.tatDj ° -21, (5% aqueous solution), Tartrate is recrystallized from 215 ml of 95% ethanol. 95 g of product are obtained with m.p. eO-eS C. After recrystallization, the melting point of the product is 102-103 C. It contains 1 mole of water, 7 (5% aqueous solution). 94 g of tartrate is dissolved in slightly warm water. The base is precipitated by the addition of a 20% ammonia solution and then extracted with ether. 52.5 g of base are formed. -57.5 ° (5% dimethylformamide solution). 51 g of base (0.16 mol) are dissolved in 150 ml of ethyl acetate. A solution of 5.9 g of dry hydrochloric acid in 65 ml of ethyl acetate is added, the hydrochloride is crystallized and filtered off, washed with ethyl acetate and dried in a drying oven at 40 s. The result is 41.5 g C; the left product with so pl. 117-119 C ,, 4 (5% aqueous solution). Yield 22%. / Example 10, 1-Ethyl-2- (2ethoxy-3, 5-dichlorophenoxyethyl) pyrrolidine. A solution of sodium ethoxide is prepared from 9.2 g of sodium and 120 ml of absolute ethanol, and then 83 g of 2-ethoxy-3, 5-dichlorophenol (0.4 mol) is added. The alcohol is distilled off and then 240 ml of dry xylene is added. The last traces of alcohol are removed by azeotropic distillation. After cooling, 71 g of 1-ethyl-2- (5-chloroethyl) pyrrolidine (0.4 mol + 10% excess) is added and the reaction mixture is kept overnight. The mixture is heated to boiling point, which is maintained for 4 hours, and then cooled and dissolved in 600 ml of water and 30 ml of concentrated hydrochloric acid. The aqueous phase is decanted and filtered with carbon black, and then the base is precipitated by adding 60 ml of concentrated ammonia solution. It is decanted. The aqueous solution is extracted with methylene chloride and the organic phase is dried carboxy potassium atom. After removal of the solvent, the residual product is subjected to distillation under vacuum. 101 g of base are obtained with a boiling point of 198-200 ° / 8 mm Hg. The base is dissolved in 300 ml of absolute ethanol. A solution of 58.5 g of anhydrous citric acid in 200 ml of ethanol is added to the resulting solution. The resulting citrate is isolated by filtration, washed with alcohol and air dried, T, pl. 95-100s. After filtration with carbon black, the product is recrystallized from 130 ml of ethanol. 124 g1-ethyl-2- (2-ethoxy-3, 5-dichlorophenoxyethyl) are obtained. Pyrrolidine citrate with m.p. 95-100 C. The yield is 59%. Example 11. 1-1, cyclohexyl-4 (2-methoxy-3, 5-dichlorophenoxy) -hexamethyleneimine, 1-cyclohexyl-2- (2methoxyg, 5-dichlorophenoxyethyl) pyrrolidine. Analogously to Example 1, 116 g of 3,5-dichlorogvayacol (0.6 mol) and 148 g of 1-cyclohexyl-2i 2.-CHLEPTHYL pyrrolidine are reacted (0.6 mol + + 11% excess), resulting in 233 g of the product, which is, as established by those analyzes, a mixture of two isomers: 1-cyclohexyl-4- (2-methoxy3, 5-dichlorophenoxy) hexamethylenimine and 1-cyclohexyl-2- (2-methoxy-3, 5-di chlorophenoethyl) pyrrolidine. 233 g of base are dissolved in 450 ml of water and 53 ml of concentrated hydrochloric acid. The solution is cooled and a seed crystal is introduced to initiate crystallization and the mixture is then incubated overnight. 163 g of hydrochloride is formed. The hydrochloride contains in fact only the hexamethylene amino derivative. The hydrochloride is recrystallized by filtration with carbon black, resulting in 150 g of 1-cyclohexyl-4- (2-methoxy3, 5-dichlorophenoxy) hexamethylenimine chlorine hydrate, mp 174-17 bs. The yield is 61%. The aqueous solutions are then filtered using carbon black and converted to alkaline by the addition of a 20% ammonia solution. The oil is decanted and extracted with ether. The resulting ethereal solution is dried with potassium carbonate and then the ether is distilled off at the final stage under vacuum until a constant weight is obtained. The resulting weight is 92 g. 86 g of base (0, 23 mol) are dissolved in 260 ml of acetonitrile and 53 g of phosphoric acid (, 23 mol). The phosphate formed is precipitated as an oil, which crystallizes after overnight storage. This phosphate is separated by filtration, washed with acetonitrile, dried in air and then under vacuum over sulfuric acid, but the resulting product is semi-crystalline. It is dissolved in 150 ml of absolute ethanol and left overnight. Then it is crystallized, separated by filtration, washed with ethanol and dried at 40 ° C. 55 g of 1-cyclohexyl-2- (2-methoxy-3, 5-dichlorophenoxyethyl) pyrrolidine bisphosphate are formed with mp 138-138.5 ° C. Yield 17%. Example 12. 1-Cyclopropylmethyl-4- (2-methoxy-3, 5-dichlorophenoxy) hexamethyleneimine, 1-cyclopropylmethyl 2 (2-methoxy-3, 5-dichlorophenoxyethyl) pyrrolidine. Analogously. Example 1 carried out the reaction of 174 g of 3,5-dichlorogvayacol (0.90 mol) and i86 g of 1-cyclopropylmethyl-2- (2-chloroethyl) -pyrrolidine (mol + 10% excess), which resulted in 329 g The product {theor.310 g), which was determined by TLC analysis, is a mixture of two isomers: 1-cyclopropylmethyl-4- (2-methyloxy-3, 5-dichlorophenoxy) heximethylamimyka and 1-cyclopropylmethyl-2 - (2methoxy-3, 5-dichlorophenoxyethyl) pyrrolidine. 328.5 g of base are dissolved in 500 ml of ethanol, and 173 g of citric acid (0.8 mol) dissolved in 1000 ml of ethanol are added to the resulting solution. The citrate slowly crystallizes. It is isolated by filtration, washed with 300 ml of ethanol and dried at. 389 g of citrate are formed with a mp. 60-65 ° C, which, as determined by TLC analysis, is a mixture containing a greater amount of hexamethyleneimine derivative than the pyrrolidine derivative. This citrate is recrystallized by filtration on carbon black successively from 780 ml of acetonitrile, 510 MP and then 646 ml of methyl ethyl ketone. 189 g of 1-cyclopropylmethyl-4- (2-methoxy-3, 5-dichlorophenoxy) hexamethylenimine with m.p. 71-73 C. Alcohol liquids after crystallization of citrate are concentrated to a volume of 280 ml. They are diluted with 1 l of water and the solution is made alkaline by the addition of a 20% ammonia solution. The oil is decanted off and extracted with miltyl chloride. The organic phase is dried with potassium carbonate and then distilled off with methyl chloride in the final stage under vacuum until a constant weight is obtained. The resulting weight is 76 g. Dissolve 69 g of base (0.2 mol) in 275 ml of absolute ethanol. 23 g of fumaric acid (0.2 mol) is added and the mixture is heated to form a solution. The resulting Hfcjft solution is then cooled. The fumarate is crystallized, filtered off, washed with 60 ml of ethanol and dried in a drying oven. The resulting weight is 65 g. This product is a mixture containing predominantly a pyrrolidine derivative. It is recrystallized by filtration with carbon black from 130 ml of 95 ° ethanol. As a result, 54 g of 1-cyclo-1-propylmethyl-2- (2-methoxy-3, 5-dichlorophenoxyethyl) pyrrolidine fumarate with mp 162-163 ° C is formed. As a result of TLC, the presence of the hexamethylene derivative was not detected. Example 13. Preparation of 1- (1-cyclohexenylmethyl) -2- (2-me ± oxy, 5-dichlorophenoxy-ethyl) pyrrolidine, - (1-cyclohexenylmethyl) -4- (2-methoxy-3, 5-dichlorophenoxy) azefine. 60 ml of ethanol is poured into a 250 ml albu flask equipped with a stirrer, an thermometer, a cooler and a dropping funnel, then 1.4 g of sodium are added in portions. After complete aeration, 11.6 g of 3.5 of ihorgvoyacol are added and then the solvent is evaporated under vacuum.
The quench residue is dissolved in 60 ml of DMF, the solution is heated to about 100 ° C, then a solution of 8 g (1-cyclohexenylmethyl} 2-pyrrolidinyl) chloroethane (0.030 mol) in 40 ml of DMF is added dropwise.
Heating is continued for 2 hours, then the solvent is evaporated to dryness under vacuum. The residue is heated with 300 ml of water, then the mixture is made alkaline with ammonia. The suspension is extracted three times with 100 ml of ether and the organic layer is washed with 100 ml of water. The ether solution is dried over magnesium sulfate, then the solvent is evaporated to dryness under vacuum. Forms 12 g of the product. . Using the NMR spectrum, it was established that it is a mixture containing about 30% of the pyrrolidine derivative and 70% of its azepine isomer.
The mixture is dissolved in 40 ml of methyl ethyl ketone and acidified to pH 1 with concentrated hydrochloric acid in isopropanol. The crystallization is carried out by adding a seed crystal, then the mixture is kept overnight. The crystals are separated by filtration, washed with isopropanol and dried in a drying oven at 60 ° C. Obtain 7.3 g of product with so pl. approximately 172 C. With the help of the NMR spectrum, it was established that it is a mixture containing 80-85% of the azephin derivative. The filtrate is evaporated to dryness, then the residue is heated with 65 ml of isopropanol. Insoluble crystals are separated by filtration with isopropanol, then dried in a drying oven at.
Forms 1 g of the product with so pl. about . Yield 8%. Using the NMR spectrum, it was established that it is 1- (1-cyclohexenylmethyl) (2 gmethoxy-3, 5-dichlorophenoxy) ethyl pyrrolidine.
The data of elemental analysis of the obtained compounds are given in table 1.
The compounds of the invention have the following numbers: 1-methyl-2-2methoxy-3, 3-dichlorophenoxyethyl pyrrolidine fumarate (racemic) (1), 1-methyl-2-2-methoxy-3, 5-dichlorophenoxyethyl pyrrolidine (orthopedic) (2 ) 1-methyl-2- 2-methoxy-3,5-dichlorophenoxyethyl} pyrrolidine (levogyrate) (3); 1-ethyl-2- 2-methoxy3, 5-dichlorophenoxyethyl pyrrolidine hydrochloride (1) acemic) {4) / 1-ethyl2-2-methoxy-3,5-dichlorophenoxyethyl | pyrrolidine hydrochloride (right rotator) (5); 1-EHYL-2- 2-methoxy-3, 5-dichlorophenoxyethyl pyrrolidine hydrochloride (levogyrate) (6), 1-allyl-2-2-methoxy-3, 5-dichlorophenoxyethyl 1-pyrrolidine fumarate (racemic) (7) 1-ETHIL-2- 2-ethoxy-3, 5.-dichlorophenoxyethyl} pyrrolidine citrate (racemic) (8) 1-ETHIL-2-3,5-dichlorophenoxyethyl pyrrolidine {racemic) (9) j 1-methyl 2-2 methoxy-3, 5dibromophenoxyethyl pyrrolidine fumarate (racemic) (10) J 1-methyl-4-2methoxy-3, 5-dichlorophenoxy hexamethylenimine; hydrochloride (11), 1-allyl4-2-methoxy-3, 5-dichlorophenoxy hexam; € tylenmine citrate (12) ; 1-cyclohexyl-4- 2-methoxy-3, 5-dichlorophenoxy hexamethylenimine hydrochloride (13); 1-cyclohexyl-2-1 2-methoxy 3, 5-dichlorophenoxyethyl pyrrolidine bisphosphate (14), 1-cyclopr 6pilmethyl-4 2-methoxy-3, 5-dichlorophenoxy hexamethyleneimine citrate (15); 1-cyclopropylmethyl-2- 2-methoxy-3, 5-dichlorophenoxyethyl pyrrolidine fumarate (16).
Toxicity DLjfj mouse, mg / kg (base), are given in table.2.
The local anesthetic properties of the compounds of the invention are proven by tests described below.
 Local surface anesthetic properties are established by Renier's method, by investigating the suppression of the oculopalpebral reflex on the rabbit's cornea.
The beret group of ten rabbits The depth of the anesthetic effect on the cornea after infusing two drops of an aqueous solution of the product into the eye is investigated by comparing with the depth of the anesthetic effect on the cornea of an aqueous solution of cocaine hydrochloride at various levels of concentration. The test is carried out by a recresisting experiment method. The average number of strokes to the cornea of the eye per hour, which does not cause any reaction, indicates the intensity of the anesthetic effect. Therefore, it is possible to estimate the depth of the anesthetic effect as a percentage depending on the concentration and to determine graphically the CE 50 indicator. The CE 50 indicator is used to indicate the concentration of the solution, which, after the introduction in a given volume, reduces the sensitivity of animals by 50%. Activity indicators are determined by the formula
CE 50 for the well-known anesthesia EY 2 ESC P2555-E5.
for the product being tested
The activity index as a surface anesthetic in rabbits is the following: for compounds 1-7, respectively, 1.36, 1.72; 1.92; 4.65; 3.52; 2.12; 1.84, for compound 11-1.56, for compound 16-5.68.
The activity of rio transmission;) the presence of a detecting effect is investigated in the following way.
A local anesthetic, injected into the rat's front paw along the seminal nerve at a dose of 1 ml, has an anesthetic effect on the nerve endings, which is characterized and measured by pinching the middle finger of the rat's hind paw.
The compounds of the invention or the control anesthetic (xylocaine) are administered in a volume of 1 ml in predetermined concentrations to a group of ten male rabbits.
After 30 minutes, 1 hour, 2 hours, and 3 hours, after insertion, three middle fingers of the hind pincer are pinched and the animal responds positively to each spike by the fingers. By summing up the positive reactions in ten animals, it is possible to obtain an anesthetic effect in percent. The CE 50 is then determined graphically.
The activity indicator of anesthetic transmission for rats is the following: for compounds 1-6, 3.31, 4, respectively; 2.1; 2.4; 4.14; 3.4, for compound 8 - 2.44, for compounds 11 and 12, respectively, 2.4 and 2.8.
The spread of anesthesia in Guinean pigs was studied in accordance with the procedure based on the disappearance of the skin reflex, which is manifested in Guinean pigs under mechanical stress (. Pharmacol. Exp. Ther., Vol. 85, 1945, p.78-84) .
Again in the experiment, groups of ten adult males of Guinean pig were used and the day before the experiment, the bristles were gently removed from the 16 cm surface on the back. Inks were used to define four ABCD areas: A - left front area, B - right front area, C - left rear area, D - right rear area.
In the center of each area, a check is made for the presence of a dermal reflex; gz with a single injection prick beam. Then, 0.2 NUi of the anesthetic solution is injected in isotonic i solution for injection of sodium chloride as an injection. After 5 min, the center of the intradermal orifice begins to be excited regularly with a frequency: 1 excitement every 3 seconds until the reflex is restored, or if the anesthetic is
0 total, the number of stimulations is 6. The anesthetic exposure test continues every five minutes for 30 minutes.
The control compound is procaine.
five
Groups consisting of 10 guinea pigs are taken for each given concentration of procaine and a compound according to the invention, 5 the animals are administered a compound according to the invention
0 in the region of L and C, and the remainder is injected with procaine in the region. B and B. A cross-experiment is conducted the next day, when the areas for administering the drugs change.
five
Two more groups are taken and the same experiment is repeated with two different concentrations of the compound, the invention and procaine. At the same time, the average excitation effect
0 obtained for 10 guinea pigs, calculated for each concentration level.
i Determination of anesthetic effect in percent depending
5 of the concentration makes it possible to determine the indicator CE 50 graphically.
The index of anesthetic transmission activity in Guinean pigs is as follows: for compounds 1-3, respectively, 3.58, 3.1, 4.2, for compounds 5 and 6, 1.65 and 2.69; for compounds 8-10, respectively 5; 1.8; 3.17 and for compounds 14 and 16 4.07 and 2.55.
five
The results of the tests prove the anesthetic activity of the compounds according to the invention, which is 2-4 times higher than the average activity
0 known anesthetics (xylocaine, procaine and cocaine).
Table 1
Continued table. 1 Number with dineni 12 13 14 15 16 19108550720,. . Continued table. 2 T- --- - --- - --- .. “-.- .----“ - - - - - “..., - IIj IV P SC. ro t-Jl) 1 (31.6-36182-195. 60% eortality480-531 15.3-14.8 91.1-86.5 10% mortality 455-464 19.7-19.388 , 4-88550-591206-216 18.5-19,1122-116411-404270-254 22.9-26.9142-136479-512293-303 at a dose of 1400 mg / kg at a dose of 180 mg / kg

权利要求:
Claims (1)
[1]
METHOD FOR PRODUCING HETEROCYCLIC PHENOXYAMINE DERIVATIVES of the general formula where A is hydrogen, methoxyl or ethoxyl;
X is chlorine or bromine, '
R is methyl, ethyl, allyl, cyclohexyl, cyclopropylmethyl or cyclohexenylmethyl, m is 0 at η = 2;
η - 0 for w = 2, or their optically active isomers, or their salts, characterized in that the sodium phenolate of the general formula _n where A and X have the indicated meanings, are reacted with a compound of the general formula ΐ in where R has the indicated meanings
I is halogen, and the target product is isolated in free form or in the form of a salt, or separated into optical isomers.
Priority by signs:
07/06/79 when
A is hydrogen, methoxyl or ethoxyl; X is chlorine or bromine;
R is methyl, ethyl, allyl or cyclohexyl.
01.104.80 at
A is methoxyl or ethoxyl.
X is chlorine or bromine,
R is cyclopropylmethyl.
>

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法律状态:

优先权:

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申请号 | 申请日 | 专利标题

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FR7917610A|FR2460935B1|1979-07-06|1979-07-06|

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FR8007352A|FR2479218B2|1980-04-01|1980-04-01|

---