SU578880A3 - Method of preparing benzilaminooxazolines or their salts or their optical isomers - Google Patents

Description

solvent at 6–20 ° C and the co-halogenoalkylurea obtained with the general formula C — HH – C – fm – CH – CH – Hai I I I I «I LR, R, where X, RI, Rj, RS, R4, B and Hal have the indicated meanings, cycl. in aqueous medium at boiling of the reaction mass. The resulting compound of the general formula) is isolated in the form of a base or a salt or is separated into its optical isomers. The compounds of general formula (13 /) are cyclized by boiling the reaction mass in an aqueous medium in the presence or, in the absence of a basic agent, capable of fixing the hydrogen acid molecule formed during the cyclization reaction. A basic agent is a mineral agent, such as alkali or alkaline earth metal carbonate, alkali metal bicarbonate, alkali metal hydroxide, alkali metal oxide, magnesium or aluminum oxide, magnesium carbonate or phosphate, basic aluminum salt, or an organic base, such as dialkylamine, trialkylamine, dimethylaniline pyridine base. The compounds of general formula (I) are separated into optical isomers by salt formation with an optically active acid, for example, d-tartaric, N, N: AHMeniimHHHoA, abietic, d-or -chrysanthemir, d-glucose 1 - phosphoric, Y-methoxy-sulfur or d - dibenzoylvinovna. Section 9 can also be carried out on an original substance, for example, l-trifluoromethylZen, of the general formula (II). The starting benzylamines of the general formula (P) are obtained in a conventional way, starting from 1 - halogen 3 tIl (b) rmetch1benzene of the general formula which interacts with metal or metalloxys in the presence of cadmium chloride, then with halogenang acid of the formula RjCOCI with a common ketone of general formula c -Rt W.-it is reduced to form hydroxylated by the general formula which is converted to the corresponding amine by formation of an isocyanate, conversion to a caromate and reduction. When RZ is hydrogen, compounds of the general formula (U) are obtained by forming oxime from a ketone of general formula (V), then reducing the oxime of the general formula with an alkaline metal in an alkanol or mixed alkali metal hydride. Magnesium, zinc, cadmium, mercury, copper or tin are used as metal or metalloid. Deputy X can occupy any position in the benzene cycle, with the exception of positions 1 and 3 on the benzyl chain. Lower alkyl in the above radicals contains 1-6 carbon atoms, for example methyl, ethyl, isopropyl or n-hexyl; lower cycloalkyl contains 3-6 carbon atoms, in certain cases substituted by one or more lower alkyl, for example 1,1-dimethylcyclopropyl, 3,3,5 trimethylcyclohexane or cyclopengyl. Example 1. DL - N - (a - cycloprod) - (3 trifluoromethylphenyl) - methyl) - 2 - aminoxazolium A a - Cyclopropyl - (3 - trifluoromethylphenyl) Prepare an organomagnesium derivative 1 (trifluoromethyl) - 3 - bromobenzene in as a 3 M solution in ether from 225 g of 1 - (trifluoromethyl) - 3 bromobenzene. Then the organo magnesium derivative is obtained in c. the organic cadmium derivative by adding 0.53 mol of cadmium chloride at 0 ° C, the mixture is refluxed at the boiling point of the solvent for 60 minutes, the ether is distilled off, gradually replaced by a double volume of benzene, 105 g of cyclopropanecarboxylic acid chloride are added dropwise at a temperature below 30 ° C. Then it is stirred for 1 hour and the excess reagent is decomposed by carefully adding hydrochloric acid. After dilution with water, the benzene phase is separated, which is washed with water, dried and distilled under vacuum. By fractional distillation, 90 g (42%) of the desired product are obtained, b.p. 115-118 ° C, n 1.4811. B. a-Cyclopropyl - (3 - trifluoromethylphenyl) ketoxime. 75.8 g of a - cyclopropyl - (3 - trifluoromethylphenyl) - ketone are treated with 78 g of hydroxylamine hydrochloride in 280 ml of a mixture of equal parts of pyridine and ethanol at reflux for 16 h, obtaining 62 g of oxime as a mixture of CUH-iang isomers , tl. 60-61 ° C (pentane).

B. DL - a - cyclopropyl - 3 - trifluoromethyl-5-benzylamine.

61 ha of cyclopropyl - (3 trifluoromethylphenyl) - ketoxime is dissolved in 450 ml of ether, 20 g of lithium aluminum hydride are added and refluxed for 3 hours. After removing the excess reagent and solvent, 41.8 g (65%) of amine are obtained, t .kip. 106-110 ° C / 13 mmHg, 1.4775. The product is purified, converting to hydrochloride, so pl. 260 ° C (sublimation).

D. 1 - (/ 3 - chloroethyl) - 3 - (((a - cyclopropyl) (3 - trifluoromethylbenzyl) - urea.

4.3 g - a - cyclopropyl - m - trifluoromethylbenzylamine is dissolved in 8 ml of tetrahydrofuran, 2.1 g of | 3-chlorosyl isocyanate dissolved in 4 ml of tetrahydrofuran are added at a temperature not exceeding 0 ° C. The mixture is left to stand for 4 hours, then the solvent is distilled off under vacuum and 6.2 g (97%) of urea are obtained. After recrystallization from a mixture of cyclohexane - benzene, the expected product is obtained from mp 91-95 ° C.

D. DL - N - (a - cyclopropyl) - (3 Trifluoromethyl) - methyl - 2 - aminooxazolin.

14 g of 1 - (| 3 chloroethyl) - 3 - (a - cyclopropyl) - (3 - trifluoromethylbenzyl) - urea are suspended in 60 ml of water and boiled under reflux for 30 minutes, gradually dissolving the product. After cooling, the clear solution is made alkaline with 4 ml of ammonia. The aqueous phase is extracted three times with ether, the ether solutions are separated, dried and distilled under vacuum. The dry residue is taken up with diisopropyl ether and 7 g (60%) of the pure product are creeping out, so pl. 84-86 ° C.

The IR spectrum shows the presence of a C-N bond at 1685.

Example 2. 1 - (- chloroethyl) - 3 - (and alkali propyl) - methyl - (3 - trifluoromethylphenyl) - urea.

And, analogously to example 1 G, urea is obtained with a quantitative yield. The product is used for the next step.

B. dl - 2 - (a - cyclopropyl) - 2 - (3 trifluoromethylphenyl) - 2 - (oxazolyl - 2 amines) - ethane.

Analogously to Example 1, D is obtained with a yield of 75% d (-2 - (Q - cyclopropyl) -2 - (3V trfluoromethylphenyl) -2 - (oxazolinyl - 2 amino) - ethane, mp PL 112-119 ° C, mol. weight 29830 Found,%: C 60.27; H 6.05; N9.35. CisH.vNjO

Calculated,%: C 60.39; H 5.75; N 9.39

Example 3. Ng (Q - cycls tropil) - (3 phfluoromethylphenyl) - methyl - 2 - aminooxazoin, levs rashayuvsh.

The synthesis is carried out on the basis of a degrading (3 trifluoromethyl) -a-cyclopropylmethylamine, analogously to example 1, which is separated using d-tartaric acid, while controlling the purity by gas chromatography of the split optical isomer using a Mosher reagent.

Thus, the following isomers are obtained:

programing (3 - trifluoromethylphenyl) - a - cyclopropylmethylamine, (+ 35.6 ° (g 1; ethanol),, 4 °;

N - ((a - cyclopropyl) - (3 - trifluoromethylphenyl) - methyl- - 2 - aminesuxase in, levogyrate, mp 59-68 ° C, -21 ° (c 1; ethanol), asj | -86, 4 ° (with 1; ethanol).

Example 4. N- (Q-cnclopropyl) - (3-trifluoromethylphenyl) -methyl-2-aminooxazoline, right-rotator.

Analogously to example 3 receive;

(a-cyclopropyl) - (3 - trifluoromethylphenyl) -methylamine, levorotatory, (a) -35.8 ° (c1; ethanol), -129.5 ° (c1; ethanol);

iea

N - (a - cyclopropyl) - (3 - trifluoromethylphenyl) - methyl - 2 - aminooxazolin, dextrorotatory, so pl. 59-65 ° C, Q 421.5 ° (c1; ethanol), 5 (ethanol).

EXAMPLE 5: 2- (3-trifluoromethylphenyl) -2-(oxazolinyl-2) -amino-ethane.

Analogously to example 1, starting from 2- (3- trifluoromethylphenyl) -2-aminoethane, d, l-2- (3-trifluoromethylphenyl) -2- (oxazolinyl -2) -aminoethane, m.p. 89-94 ° C (dashzopropyl ether), which is dissolved in 1N. hydrochloric acid. After evaporation of the solvent to dryness, the hydrochloride of the desired product is obtained, mol. Weight 258.23. 5Found%: C 55.69; 5.23; N 10.78

C.zHijNjO,

Calculated,%: C 55.80; H 5.30; N 10.82. Example 6. d, l - N - (a - vdclopropyl) - (3-trifluoromethyl - 4 - fluorophenyl) - methyl - 2 -aminoxazoline.

Analogously to example 1, starting from 1 - iodine - 3-trifluoromethyl - 4 - fluorobenzene, obtained from o-chlorotrifluoroCl-methylbenzene, is synthesized sequentially:

d, l - (3 - trifluoromethyl - 4 - fluorophenyl) - a-cyclopropyl ketoi, b.p. 104-107 ° C / 0.6 mmHg, pu 1.4805;

d, l - (3 - trifluoromethyl - 4 - fluorophenyl) - o Q - cyclopropylketoxime, so pl. below 50 ° C, yield 91%;

d, l - (3 - trifluoromethyl - 4 - fluorophenyl) -. and Tsnklopropil) - methylamine, isolated in the form of hydrochloride, so pl. Higher than 250 ° C (decomp.); d, l - I - (trifluoromethyl - fluorophenyl) - (Q - cyclopropyl) - methyl) - 3 - (D - chloroethyl) -urea, so pl. 108-111 ° C;

d, l - N - (a - cyclopropyl) - (3 - trifluoromethyl - 4 - fluorophenyl) - methyl - 2 - aminooxazole, T.PL. 81-87 ° C (pentane), mol. Weight 302.27.