SU587861A3 - Method of obtaining m-dioxane-5-methylamine derivatives - Google Patents

Description

The invention relates to a method for the additive of new compounds, derivatives of m-pyoxan-5-methipamine of the general formula /,. en2-o, AP-CH-CH (en-: E fi); n2-o where R is hydrogen or hydrogen; R is methyl .kp8 RB together with the adjacent nitrogen atom: ebrazu "t azvrvanvevoe, pyrrolvdinoy mon mon pi pertsyvovoe ring; R is hydrogen, is alkyp or fenip; AV phenyl, halovud, methokov-, meTNL-, trvfluoromethyl-, window-, acetoxy- (based on a scavenger) on the reaction of 1,3-aiop with formaldehyde, followed by the preparation of m-cvoxane ij, the proposed method for the production of m-dioxane-5-methylamine is that the compound of general formula B in / If eNgSN IJ r-CH-SI 4 S (1H20H where R and R are the same or different, methyl or benz p, ip R and R together with the nitrogen atom to which they are bound form an azirndine, pyrrolidine or piperidine ring; A has the above mentioned meaning, is reacted with an aldehyde of the general formula R CHO, where R is as indicated) above, in the presence of a complex boron trifluoride, when heated in an organic solvent solution with recn & a selection of the target product, influences the case of R and / or R benzyl, restoratively debenzylate and, if necessary, methylate at least one of R, and R hapidoid and select the target product itself.

Usually, the reaction of npOBOt T at the boiling point of the reaction medium in acetonitrile.

Suitable acids used to form salts include mineral acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, nitric acid, and carboxylic acids such as acetic acid, citric acid, maleic acid, and wine. Reductive debenzylation of megilbenzylamine is carried out in an amphoteric solvent, such as 95% ethanol, with a hydrogen pressure of 1-4.2 kg / cm in the presence of palladium on carbon or platinum as a catalyst to form a compound of formula J, where R is methyl and R hydrogen or the resulting debenzylated compound is alkylated with halomethyl by known methods to form a compound of formula J, where R and R are methyl. It is advisable to heat 2- (cC-dimethylamino) -benzyl-1, 3-propane-iop and 1.5 molar equivalents of paraformaldehyde tape under reflux in acetonitrile with 3 molar rn of 1 equivalents of boron trichloride etherate and chilled drink the reaction mixture into sodium bvcf sodium carbonate saturated with BORHbiR, (extract the mixture with ether, wash the extract, dry and evaporate to obtain a mass. When treating the ether solution of the separated oil with gaseous hydrogen chloride, N, K -dimethyl -o-phenyl hydrochloride is formed - m-dioxane-5-methylamine. A compound of formula T has at least one asymmetric carbon atom of the genus methylamine. Therefore, a pair of enantiomers can exist, which can be divided into Z - and D - isomers. they are pure enantiomars. Separation of compounds with three asymmetric centers is a difficult task associated with the separation of chet; pex diastereomer pairs. Usually, N, N-dimetyp-yC-phenyl-m-dioxane-5-methipamine is treated with monohydrate dibenzoip- tartaric acid to obtain dB -N, N-dimethyl-oi-f enyl-m-dioxane-4-methylamine. dE-H, M -Dimethyl-ct-phenyl-m-aioxan-4-methylamine, dissolved in ethyl acetate, is treated with 0.5 molar equivalent of dibenzoip-2-tartaric acid monohydrate in ethyl acetate. The oil immediately separates from the solution, crystallizing on addition of methanol and heating on the steam bath. After standing overnight, the salt is collected, recrystallized from ethyl acetate with the minimum amount of methanol required for dissolution, the salt is collected and recrystallized to obtain pure salt 8 -JiJ, M Dimetip-α-phenyl-m-dioxa-5-methipamine and dibenzoium / 1 - tartaric acid. This salt is suspended in distilled water, alkalinized with ammonium hydroxide, extracted with ether. the extract is washed, dried and evaporated by dosu.h. The solid t-amine is transferred to ether, treated with gaseous hydrogen chloride and the resulting pure t-K, H-Dimethyl-eC-phenyl-m-dioxa-5-methylamine hydrochloride is recrystallized from a mixture of methylacetate. . Example 1. N, K-dimethyl-oC-phenyl-m-dioxane-methylamine hydrochloride. K 2- (o.-dimethyl-idamino) -benzyl-1,3-pr | pandiol (137 g, 0.66 mol) and paraformaldehyde (ZOO g, | 1O, 0 mol) are added acetonitrile (10OO ml), added dropwise with boron trifluoride ether (BOO ml, 560 g) and heated for 2 hours with reflux. The mixture is cooled, poured into saturated sodium bicarbonate solution and extracted with ether. The extract is washed with water, dried over anhydrous magnesium sulphate and evaporated until the oil is obtained. The ether solution of the oil is treated with gaseous hydrogen chloride and get 97 g of hydrochloride, so pl. 172 C (methanol ethyl acetate). Calculated,%: C 60.58; H 7.82; N 5.43 13 9 02 Found,%: C 6O, 78; HB, 03; M 5.40. Examples 2-12. Using the method of example 1, get the hydrochloride K., Kdimetil-in- (1) -m-dioxan-5-methylamine listed in the table, as well as hydrochloride l- {d .- {m-diokan-5-yl) -4chlorobenzyl | -piperidine, m. pl. 195 ° C (decomp.). Calculated,%: C 57.84 jH, 6.98; N 4.22j and 21.34. Found,%: C 58.14; H 7.01; M 4, DA; ё 21,42. Hydrochloride 1-cL- (m-dioan-5-yl) -beN and / D-pyrrolidine, so pl. 2 ° C (decomp.). Calculated,%: C 63.48; H 7.81; N 4.94. 15 jN02-C Found,%: C 63.73; H 8, O8; H 5.2O. N, M-2-trimethyl-oC- (4-meipphenip) -m-dioxane-5-methylamine hydrochloro, t. Pl. 88 ° -19 ° C; Calculated,%: C 63.04; H 8.46; , M 4.9O: .CeNO ,,. NA €. N 5.14. Found,%: C 63.05; H 8.69; Prnmer 13. Separation of d8 -N, Mmetyp-L-Phenyl-m-dioxane-Z melaminna. dH -N iN-Dimethyl-L.-phenyl-m-dioxan-5-metnlamine {1106.5 g, 5.0 mol) is dissolved in etipatsetag (4 L), L dibeioyl-1-tartaric acid onohydrate (940 , 8 g, 2.5 mol) are dissolved in ethyl acetate (4 p) with heating. A warm solution of tartaric acid is added to the amine solution, an instant formation of oil is observed, methanop (ZOOmp) is added, heated on a steam bath (crystallization of the oil occurs) and left overnight. The resulting salt is recrystallized from ethyl acetate (5 L) with the minimum amount of methanol needed to dissolve. After the secondary recrystallization of the salt, 548 g of a salt of —N, K-dime-Tyl-L-phenyl-m-dioxane-5-methipamine and dibenzoyl-β-acid acid, m.p. 133 ° C; IbLj + 61.40 ° (, ethanol). Salt t-n. N-aimethyl-cC-phenyl-m-dioxane-5-methylamine and dibenzo-2-tartaric acid (543 g) are suspended in distilled water, alkalinized with ammonium hydroxide, extracted with ether, washed with water, dried over anhydrous magnesium sulfate and evaporated. - The obtained solid residue (210 g) is stirred in ether, treated with gaseous hydrogen chloride, the precipitate is recrystallized from methanol-ethyl acetate and 156 g of t -N, N-dimethyl-oC-phenyl-m-dioxane-5-methylamine hydrochloride are obtained. m.p. 202-203 ° C; ticCj -92.6 ° (with 51.825 mg / 5 mp, water). Calculated,%: C 60.58; H 7.72; K 5.43; From 13.75. Found,%: C 6O, 83; H 7.58; N 5.51; from 13.67. Example 14. Maleate No., 1-dimethyl- - (4-methylphenyl) -m-dioxane-5-methipamine 2-pt-Dimethylamino-4-methylbenzyl | -1,3-propanediol (2 g) and paraformaldehyde (10g in acetonitrile (50 ml) is treated with boron trifluoride etherate (3 ml), as in Example 1. An oil is extracted (2 g), which is treated with maleic acid (1 g) in ethyl acetate. After recrystallization of the salt from methanol-ethyl acetate 1.5 g of the target maleate are obtained, i.e. "138 ° C. Calculated,%: C 61.52; H 7.17; K 3.99. Found,%: C 61.6O; H 7.38 ; K 3.8O.GG and meper 1 5. Dihydrochloride M, M-iimethyl-C- (: -pyridyl) -m-di oxane-5-methy l amine. Similarly to example 1 of 2- (e1 -pimitipamino- (3-pyridip) -metide -1, 3-propane (7 g), steam a (|) orm aldehyde a (30 g) and boron trichloride etherate (5O ml) in acetonitrile (10O mp) gives a free base (6 g), which is treated with gaseous hydrogen chloride in the ether, to give mp 1E ° C 1 g of the desired digitsrochloride (methanol-ethyl acetate). Calculated,%: C 48.82; H 6.83; H 9.49. NarDEN,%: C 48.65; H 0.69; H 9.60. Example 16. M, N -2-Trimetip-α-phenyl-m-dioxan-5-methyl). To a solution of 2- (dL-dimethylamino) -becip--1,3-propanediol (2.5 g, 0.012 mop) in acetohydric (25 ml), water (7.68 g, 0.48 mop), acetaldehyde ( 10 ml) and boron trichloride boron (3.01 ml, O, O24 mol), stirred overnight, heated for 1 hour on a steam bath, Cooled, poured into ammonium hydroxide and extracted with ether. The extract is washed with water, dried over anhydrous magnesium sulphate and evaporated to dryness. The residue is recrystallized from hexane and get 0.44 g of the target substance, so pl. - 14O-143 C. Calculated;%: C 71.46; H 9, OO; To 5.85. 14 21 02Found,%; C 71.22; H 8.92; N 5.68. Examples 17 and 18. As in Example 16, from 2- (dC, -dimethylamino) -benzyl-1,3-p | ) 6 pandiol and the corresponding aldehyde get N -, N-cymethyl-2-ethyl - clL-fpIsl-mdiocan-5-methylamine, m.p. 95-98 ° C Calculated,%: C, 72.25; H 9.30; N 5, f; 2. 15 23 02Found,%: C72.49; H 9.60; N 5.69. N, N -Dimethyl-o1.-2-diphenyl-m-diox :) 5-methylamine, t. Pl. 1O5-1O8 C Calculated,%: C 76.74; H 7.8 O; N 4.71. . Found,%: with 76.91; H 7.62; N 4.45. Example 19. N-metip0 hydrochloride (. -Chenyl-m-dioxane-5-methylamine. 2- (ei-K-Methylbenzylamino) -benzyl-1, .C propandiop (12O g), aldehyde vapor (100 g) and The efflux of three-boron boron {20 (ml) is heated overnight with a reflux plug in acetone (500 ml), poured into ammonium hydroxide and, after subsequent processing, free oil (84 g) is obtained in the form of oil. From this, 25 g hydrochloride of N-benzkl-N-metn p-in-C-fnip-m-pibksai-b-metnpamina, TPP 193-l95 ° C, identified by NMR-spectroscopy ..

K -Bvn8vl-L -methyl-vC-phenyl m pyoks-5-methylamine (18 g) gndroge1iruyutot at 5 pressure of 4.2 kg / cm in ethanol (8O ml) in the presence of 5% -Hori. palladium coal (Oh, 9g)

Claims (1)

-as a catalyst at 35 ° C for 1.25 hours. The catalyst is filtered off. The "{daptrate" is evaporated, the remaining oil is dissolved in ether, the solution is treated with gaseous hydrogen chloride and 3j7 g of the desired hydrochloride are obtained, i.e. 155-157 with (ethanol-ethyl acetate). Claims 1. Method for producing m-lioxan-5-mpi-imine derivatives of the general formula [I / HZ-OV (JH J; JH-R H2-0-0 where R is hydrogen or methyl; R is methyl and R and R together with the nitrogen atom with which they are bonded form an aziripin pyrrolipin or piperi-pyr ring; R is hydrogen, C-Cf-alkyl; py-phenyl; Aif-fenEp, halo-, methyltrifts-mettip-, acetoxy- and benzyloxypheny, Institute III-pyridyl, provided that Af substituted phenyl, the substituent is not in the meta position of the benzene ring, characterized in that the compound of the general formula B / 1G (jHeOH "I Af-dH- (iH 5c. 1 where R and R - identical or different, methyl or benzyl, or F and R together with the nitrogen agome to which they are bound form an aziripine, pyrrolidine or pi piperidine ring; A | has the aforementioned 1e values; under the BibrajQT interaction with an aldehyde of the general formula R CHO hee R - as as indicated above, in the presence of boron trifluoride complex, when heated in an organic solvent medium, followed by elution of the target product or in the case when R and / or R is benzyl, the reducing agent debenzylates and, if necessary, methylates at least one of R and R loidalkilom and isolated tsepevoy product. 2 The method according to claim 1, characterized in that the heating is carried out at the boiling point of the reaction medium. 3. The method according to 1, that is, that acetonitripe is used as an organic solvent. Sources of information taken into account in the examination; 1. Elderfield, Heterocyclic Compounds, M. Foreign Literature, 1960, V. 6, p. 31.