Method of preparing aryltrifluoroethylamines or their salts or their optical isomers or mixtures of

专利摘要:
Certain phenyl amines have been prepared wherein the "methyl" carbon is substituted with a polyfluoroalkyl radical. The compounds form acid addition salts, exist in resolvable stereoisomeric forms, and are useful for treating hypertension. Formulations for human and veterinary medicine are described, as well as methods of use.
公开号:SU725561A3
申请号:SU772481553
申请日:1977-05-24
公开日:1980-03-30
发明作者:Мален Шарль；Роже Пьер；Лоби Мишель
申请人:Сьянс Юньон Э Ко., Сосьете Франсэз Де Решерш Медикаль (Фирма)；
IPC主号:

专利说明:

in iyertns organic solvent at a temperature, then obtained (i-haloalkyl urea of the general formula IV h ;.) -CK- (CFi) n-CF3 in: y-C-Sh1H g) Cs A south and by which the substituents A, B, R R2; R, Rat, pit have the above (values), are cyclized by heating at a temperature of 50-1SO C, and the target products are isolated in free form or in the form of their salts, or their optical isomers, or mixtures of their optical isomers. Formula I with an isocyanate of general formula III is carried out in an inert solvent such as a cyclic or linear ester. The cyclization of halogenoalkyl urea common IV is carried out preferably in an aqueous medium and in the presence or absence of a proton acceptor, for example an alkali metal carbonate or trialkyl The target products are isolated in free form or in the form of their salts with acids, such as hydrochloric, hydrobromic, phosphoric, sulfuric or nitric, formic, acetic, n-dipropyl acetic, tartaric, lemon maleic, itaconic, benzoic, thiazole-5 carboxylic, nicotinic, glucose-1-phosphoric, methanesulfonic, ethanesulfonic, isotionic or benzene sulfonic acid “Example 1. dE-2-Cci - (Trifluoromethyl benzyl tino) -oxazoline, Step A. A solution of 7.4 g of dC- (c6- fenclftrifluoroethyl) -amcna in 40 ml of ether of okla is served before and a solution of 4.3 g of isocyanate is added Prolactyl in 25 m of ether for 30 minutes. The reaction mass was stirred for 24 hours at room temperature. Then the precipitate is filtered, washed with ether and dried. Yield: 7.9 g of N- {c6-phenIltrifluoroethyl) -N-p-chloroethylmoleum (67%); tpl 1 27-1320С. Stage B.7, b g of N- (cX phenyl trifluoro ethyl) - M- (p-chloroethyl) -urea obtained in step A are suspended in 60 ml of water and 4.3 ml of triethyl amine are added. The mixture is heated to boiling, kept at this temperature and cooled to room temperature with stirring for 30 minutes. The precipitate formed is filtered, washed until neutral wash water is obtained and dried under vacuum. The output of 6.3 g of 2-dr (trifluoromethylbenzylamine) -oxazoline - (95%). For analysis, the product is recrystallized from isopropanol; t, pl, 162-1b8s (after sublimation). . 4 Found, C 53.98; H 4.55; N 11, 34. C., H., F, N O (244.22), Calculated,%: C 54.10; H 4.54; N 11.47. Example 2, (- (Trifluoromethyl) - (3-trifluoromethylbenzylamino) -oxazoline. Stssi A, (3-Trifluoromethylphenyl) -trifluoromethyl ketoxime.) In 250 ml of a mixture of pyridine and ethanol dissolve 7.8t of hydroxylamine hydrochloride and 7 g (m-trifluoromethylphenyl) - trifluoromethylkeone, The reaction mass is boiled for 16 h, then cooled and diluted with 100 ml of water. The precipitating oxime is filtered, drained, washed with water several times and dried in vacuum. Yield 42%; mp. Stage B. dC-oL- (3-trifluoromethylphenyl) - (trifluoroethyl) -amin 2.5 g (3-trifluoromethylphenyl) trifluoromethyl ketoxime, semi Suspended in stage A are suspended in 40 ml of isopropyl ether, 4 gum of lithium hydride is added, then the mixture is kept at boiling for 3 hours. After cooling the reaction mixture, an aqueous solution of tartaric acid is added, alkalized with sodium hydroxide and the ether phase is separated decantation. The aqueous phase is extracted again with isopropyl ether, the extracts are combined, washed with water, dried and the solvent is distilled off. The oily residue is purified by fractional distillation. The product is distilled at 82-83 ° C (15 mmHg, st); d - 1,4250, Stage D, dP-2-c (.- Trifluoromethyl- (3-trifluoromethylbenzylamino) -oxazblin. Same as described in example 1, step B, from dC-N- s .- (3-trifluoromethylphenyl) - trifluoroethyl -N- (p-chloroethyl) -urea gives the title product; m, 129-132 ° C; Found,%: C 46.45; H 3.48; N 8.85. C 2HFN20. C 46.16; H 3.23; Calculated,%: N 8.96, Example 3, de-2- (c (, - Trifluoromethylbenzylamino) -4,5,6-tetrahydro-1, 3-oxazine, Step A , N- (d-Phenyl- (trifluoroethyl) -N - (; f-chloro-propyl-urea. As described in Example 1, Step A, from dE-c-phenyl- (trifluoroethyl) -amine and isocyanate-chloropropyl is obtained with quantitative you One named Compound, Step C. N-tcf- (3-Trifluoromethylphenyl) -trifluoroethyl JN - (p | -chloroethyl) urine .In the same way as described in Example 1, Step A, the named compound is obtained in quantitative yield; 124-128C,
Stage B. dE-2-ct-Tfifopromomethylbenzylamino-4, 5,6-tetrahydro-1,3-oxaein. Similar to that described in example 1, get the target product. Yield 30%; m.p. FROM FROM (from isopropyl ether).
Found,%: C 55,32; H 5.29; N 10.65.
 i-6 NaO Calculated,%: C 55.81; H 5.01;
N 10.85. ,
Winner 4. Zb-2- o6-Trifluoromethyl- {4-methoxybenzylamino) -oxazolin. In the same manner as described in Example 2, from (4-methoxyphenyl) trifluoromethyl ketone, the following compounds were obtained:
a) (4-methoxyphenyl) -trifluoromethyl ketoxime so pl. 199-205s, rate 75%
B) C- (4-methoxyphenyl) - (trifluoroethyl) -amine, racemic (60% yield) b.p. 122-124C; n - 1.4805 ;. m.p. hydrochloride 208 ° C (when dry); .c) (4-methoxyphenyl) trifluoroethyl 1-S - (p-chloroethyl) -urea, racemic (quantitative); m.p. 118-124C;
. and) 2- (i-trifluoromethyl- (4-methoxybenziaminoxoxazoline, racemic; mp. 149-155 ° C (from isopropanol).
Found,%: C 52.54; H 4.98; N 10.06.
. . Calculated,%: C 52.56; H 4.69;
N 10.21.
. PRI Example 5. dC-2-ot-Pentafluoroethylbenzylamino-oxazolin. As described in example 2, the following compounds were prepared from pentafluoropropiophenone:
a) pentafluoroprospiophenone oxime ;. m.p. 53C and. yield 75%.
b) (cA - Fenilpentafthropyl) amine, racemic; bp 82-90 С
(18 mm Hg). Yield 70%.
Hydrochloride ob-phenyl- (pentafluoropropyl) -amine; incl. 178-186 ° C;
c) dC-N-ob-phenyl (pentafluoropropyl) -N- (| b-chloroethyl) urea 1a; m.p. 7882С (yield 100%);
(d) dE-2-Iod.-pentafopoethylbenzyl and MHMo-oxazoline; m.p. 181-163s (from isopropanol).
Found,%: C 49.09; H 4.01; N 9, 49.
C | 2.H.:
Calculated,%: C, 48.99; H 3.77; N 9.52,
, Example 6, dE-2- od-TpIftopomethyl- (4-chlorobenzyl) amino-oxazoline
By the method of Example 2, the following compounds were prepared from (4-chlorophenyl) trifluoromethyl ketone:
a) (4-Chlorophenyl) -triyfluoromethyl. ketoxime; mp. 68-72 ° C, Vssod 85%
B) .de-ct (4-chlorophenyl) -tiftopoethyl-amin; t. Bp. 104-107С (19 lm) m.p. 29-34s.
Hydrochloride; m.p. 182-189 0. - c) dC-N-cCr (4-chlorophenyl) "- trifluor ethyl-S- (| b-chloroethyl) -urea; m.p. 142-145 ° C. 75% yield.
d) d0-2-ob-trifluoromethyl (4-chlorobenzyl) -amino-oxazoline; m.p. 158163 ° C.
Found,%: С 47.2; H 3.61; (N9.87; se 12.81.
with, .
Calculated,%: C 47.41; H 3.62; N 10.05; SS 12.72.
P t Mime 7. 2-1oC-Trifluoromethyl., - (furyl-2) -methylamino-oxazolin. Similarly to Example 2, the following compounds were prepared from (furyl-2)-Tr14 fluoromethyl ketone:
a) (Furyl-2) -trifluoromethyl ketoxime; m.p. 103-106 ° C;
L dC-oi- (Furyl-2) - (trifluoroethyl) -amine; bp 64-68s (20 mmHg);
20
- 1.4175;
AT
, (c) d -N- oC- (Furyl-2) -trifluoroethyl -N- (ft-chloroethyl) -urea; m.p. 107 OF S. Yield 80%;
d) dt-2-ot-trifluoromethyl- (furyl-2), methylamino-oxazoline; m.p. 112 119s (after sublimation and after recrystallization from isopropyl ether).
Greater%: C 46.10; H 3.94; N 11, 81.
,,
Calculated: 110%: C: 46.15; H 3.87;
N 11.96.
2- (oC-Trifluoromethyl- (furyl-2) -methylamino-okeazolium is dissolved in a stoichiometric amount of hydrochloric acid, and a hydrochloride is obtained. Example 8. d6-2-tci-Trifluoromethyl- (thienyl-2) -methylamino-oxazoline. Stage A. (Thiimel-2) -trifluoromethyl-0-methylketoxime. (Thyen-2) -trifluoromethyl-0-methylketoxime, boiling point 78-, in the same manner as described in Example 2, is obtained from (c-thienyltiftromethylketome) and 0-methylhydroxylamine hydrochloride; 82C (20 mm Hg); P | 4.
Stage B. dE -, - (Thienyl-2) -trifluorothylamine. When reducing by diborane in the ether, o6- (thienyl-2) -trifluoroethylamine is obtained, Yield 85%; m.p. 79-81 with (20 mm Hg. Art.); P 20 - 1.6320.
, Hydrochloride; m.p. 160-162С (after sublimation).
Stage C. dC-N- o6- (Thieiyl-2) -trifluoroethyl -N- (p-chlorostil) -urea. In the same way as described in example 1, step A, of cfc- (thienyl-2) trifluorothylamine, the title compound is obtained. Yield 70%.
Stage D. de-2- e6-trifluoromethyl- (thienyl-2) -methylamino-oxazoline.
Similar to that described in example 1,
Stage B, the desired product is obtained from dK-N-oC- (thienyl-2) -trifluoroethyl-n- (p-chloroethyl) -urea; m.p. 138145 ° C (from ether),
Found,%: C 43.12; H 3.77; N 11.17; S 13.02.
Ct), f) S.
Calculated: C 43.20; H 3.63; N 11.20; S 12.82.
Example 9. Levorusculus 2-B1-trifluoromethylbenzylamino-oxalin.
Stage A. A levorotary 2-phenyl trifluoroethylamine. 45 g of ot-acid acid are dissolved in 185 ml of water and 52.5 g are poured gradually over 6 hours with phenyl trifluoroethyl amine with good agitation. The mixture was left overnight, the precipitated tartrate was filtered, drained and dried under vacuum. The output of the tartrate 51 g; m.p. 115-132p.
Two recrystallizations from water increase the melting point to 118-134 ° C. The optical purity from (.1 lbrate, determined by chromatography on a thin layer using Moser's reagent, indicates a degree of purity of 5 to 96.5%; specific rotation of o6-tartrate;
 (c - 5% MeOH);
, 5 ° (s - 5% MeOH).
 365 V
The {-tartrate is transferred to the base by the addition of sodium hydroxide with subsequent extraction with ether, distilling off the solvent. The output of 10.7 g levogyrate ct-phenyltrifluoroethylamine; m.p. 72-74 ° C (14 mm Hg). Yield 86%.
oC) g22.1 ° (s - 1% MeOH)
a (., 5 (c - 1% MeOH).
The left-handed c6-phenyl trifluoroethylamine is installed at a temperature below 3A.
Stage B. N-loL-Phenyl- (trifluoroethyl) -N- (p-chloroethyl) -urea rotating to the left. In the same way as described in example 1, collateral A, with a quantitative input, a levorotatory N-o / gPhenyl- {trifluoroethane p) -N - (chloroethyl) -urea is obtained; m.p. 149-151 ° C.
, - -38.1 °;
1cC) C, - -141 °.
Stage with. Levorotatory, α-trifluoromethylbenzylamino-oxazoline. Similar to that described in Example 1, step 84, 2-o-trifluoromethylbenzylamino-oxazoline is obtained; m.p. 125133 ° (sublimation) after recrystallization from and. opropanol.
 - -87.4 (s - 1% ethanol);
(- -335 (with - 1% ethanol).
og
Found,%: C 54.36; H 4.87; N 11.39. - -
C, N ,,).
Calculated,%: C 54,10; H 4.54; N 11.47. . .
The levorotary 2- (a1ggrift; rmethylbenei. Cel-oxazoline is dissolved in 1 and hydrochloric acid. After evaporation, 2-dL-trifluoromethylbenzylamino-c-azoline levorotrate hydrochloride is obtained.
Example 10. Progravity 2- a-trifluoromethylbenzylamino-oxazolin.
From mother liquors of levogyrate (I-tartrate-t; -phenyltriptophthylamine), o-tartrate of the right-spinning isomer is isolated, which is converted into a right-spinning o-phenyltrifluoroethylamine; boil. 74-75s (15 mm Hg);
oL - + 23.5 ° (s - 1% methanol);
(, - - 169.8 ° (c - 1% methanol).
The latter allows to obtain N-cC-phenyl- (trifluoroethyl) -N - (% -chloroethyl) -urea, rotating to the right. Yield 83.5%; m.p. 148-151 ° C; 0 - +38.2 ";
, +, 141.7 °. The latter is subjected to hot cyclization in the presence of triethylamine; m.p. the desired product 127-132 ° C (from isopropanol); ., o-Jjgp - + 87.6 °, (s - 1% ethanol); + 335.8 ° (with - 1% ethanol). Found,%: C 53, 94; H 4.84; N 11, 45.
0 C ,, H, / F, N., 0. , Calculated,%: C 54.10; H 4.54; N 11, 47.
Example 11. d-ob-Trifluoromethyl-2- (I-methylpyrrolyl-2 -) - methylamino-oxazolin.
Stage A. (K-Methylpyrrolyl-2) -trifluoro methyl ketone. 81 g of N-methylpyrrole, 241 g of trifluoroacetic anhydride and
350 ml of dichloroethane. The solution is maintained at a temperature for 12 hours. ,
P the mass of the mixture is cooled. And then the solvent is distilled off under elevated pressure, the residue is removed
ether, filtered off the insoluble part and the filtrate is dried. The resulting oily residue weighs 197 g; it is purified by fractional distillation
under reduced pressure and get
127 g of the title compound; mp. 69-7lC. Yield 72%; p - 1.4572.
The structure of the obtained compound was confirmed by IR and NMR spectra.
Stage B. (N-Methylpyrrolyl-2) -trifluoromethyl ketoxime. Similar to that described in Example 2, step A, the corresponding Lxim is obtained from (N-methylpyrrolyl-2) -trifluoromethylketone.
Yield 45%; m.p. 69-7lc (sublimation),
Found,%: C 43.72; H 3.76; N 14.36.
..
Calculated,%: C 43.76; H 3.76; N 14.58. Stage C. dC-; N-Methylpyrrolyl-2) -methyl -g / -trifluoromethylamine, as described in Example 2, Step B, 3 g of pure amine are obtained from 11 g of oxime; t kip. 84-90 C (18 mm Hg). The product is purified by transfer to the hydrochloride. T. PlLZO and then. Found,%: C 39.33; H 4.82; N 13.01; every 16.45,. nseCalculated,%: C 39.34; H 4.72; N 13.11; se 16.60. Stage D. dt-N- 2- (N-Methylpyrrolyl-2) -trifluoroethyl-N -pi-chloroethylurea. Using the method proposed in step A of Example 3, from 3.45 dC- (L-methylpyrrolyl-2) -methyl-trifluoromethylamine hydrochloride, 1.7 g of chloro-ethylurea are obtained; mp 13 136 ° C. , The structure of this compound is confirmed by the data of IR spectra. Step E. dE-aJ.-Trifluoromethyl-; - (L-methylpyrrolyl-2) methylamino oxazoline. Similar to that described in example 1, stage B, receive the target product. Yield 37%; m.p. 156167c (sublimation). This compound is dissolved in 0.1N hydrochloric acid. Found: C 48.51; H 4.94; N 16.78. . , Calculated: C 48.48; H 4.89; N 16.99, the structure of the target product is confirmed by IR spectra data. Example 12. dC-ot-Trifluoromethyl-2- (N-methy benzylamino) oxazoles Step A. dC-N-Methoxycarbonyl-oC-trifluoromethylbenzylamine. 35 g of ot-phenyl trifluoroethylamine, 20.2 triethylamine, 200 ml of tetrahydrofurm and a solution of 19 g of methyl chloroformate in 40 ml of tetrahydrofuran are successively introduced into a three-necked flask while cooling to 5-10 sec. The reaction mixture is maintained at this temperature for 1 h, then the temperature is raised to room temperature. The precipitate formed is filtered off and the filtrate is evaporated to dryness. A yield of 45.3 g of an oily residue, after recrystallization of diyl from isopropanol, gives the title compound; m.p. 90-94 s. The IR spectrum corresponds to the proposed structure. NH band at 3300 s. Carbonyl band at 1680 cm. Stage B. de-N-Methyl-cC-trifluoromethylbenzylamine. 9.5 g of lithium aluminum hydride are introduced into a three-necked flask as a solution in 100 ml of tetrahydrofuran. Then, 23.3 g of the urethane obtained in step A in 100 ml of tetrahydrofuran are slowly added. The reaction mass is heated to boiling and maintained at nppt-this temperature for 6 hours, cooled, dilute sodium hydroxide solution and water are added. The precipitate was filtered off and the filter was squeezed with several ml of tetrahydrofuran, which was then added to the filtrate. The filtrate is evaporated to dryness and 14 g of crude product are obtained. The crude product is dissolved in 30 ml of methylene chloride and treated several times with 20% hydrochloric acid. The acidic solutions are combined and alkalinized by the addition of caustic soda. The oily product is extracted with ether. The ether phase is separated, dried over sodium sulfate, and then evaporated to dryness. Yield 8.4 g of compound; m.p. 68-70s (12 mmHg); n - 1.4560. Found,%: C 57.02; H 5.37; N 7.02. .Nf ,. Calculated,%: C 57.02; H 5.37; N 7.02. . IR spectrum: no carbonyl band. Step C. d6-N-N-Methyl- (4, -phenyltrifluoroethyl) -N-O-chloroethyl) urea. As described in example 4, step A, 9.2 g of p) -chloroethyl urea are obtained; m.p. 70-80C, Found,%: C 48.36; H 4.92; N9.65; every 11.98. .CeFj. Calculated,%: C, 48.90; H 4.79; N9.51; every 12.04. Stage D. dC-Y-Methyl-2- (ct-trifluoro methyl benzylamino) -oxazolin. 77 ml of water are added to 8.2 g of dC-N-methyl-oC-phenyl trifluoroethyl)} -N -p-chloroethyl urea, 7 ml of triethylamine are added and the mixture is kept at reflux for 2 h 30 min. The reaction mixture is cooled in an ice bath, the oily product is decanted and extracted 4 times with methylene chloride. The organic phases are combined and then treated with 1N hydrochloric acid, hydrochloric acid solutions are alkalinized by the addition of ammonium hydroxide. The resulting suspension is left overnight in the refrigerator. The insoluble part is extracted with methylene chloride, the organic layer is separated, it is washed with water until the chlorine ion disappears, is dried over sodium sulfate, filtered and the solvent is distilled off to dryness in vacuum. Yield 6.1 g of oily product. The resulting compound is purified by extracting in a minimal amount of ether, the insoluble part is filtered off, the filtrate is dried and the solvent is distilled off and 4.7 g of an oily product is obtained which is soluble in most organic solvents and in 0.1 n. hydrochloric acid e. d6-N-Methyl-2- (c-trifluoromethyl-benzylamino) -oxazoline — liquid.
11 The structure of the target product was confirmed by the data of IR and NMR spectra. Example 13. 16-sb-Trifluoromethi-2- (pyrrolyl-2-) - methylamino-oxa-zoic, Using the method of example 11, the outcome and, ultimately, 11 they are 1; „..., (pyrrolyl-2) -trifluoromethylketone 0-methyl- (pyrrolyl-2) -trifluoromethyl QUTOxy; - N: - - dC -th - trifluoroethyl- (pyrrolyl-2) -methylamine ; dC -N-Cc1-t1rifluoro.methyl- (pyrrolyl-2) -methyl -N- (p-chloroethyl) -urea. -trifluoromethyl-2- {(pyrrolyl-2) -methylamino-xxazole; m.p. 125132 C (after recrystallization from ether). The product is dissolved in a stoichiometric amount of 0.1 and. Salt Yislotote, Found, lj С 46.3, h H 4 ,. N 17.82. C, H, F, N, 0. Calculated: With 46,35; H 4.33; M 16.03. ;, Pr and m and p 14. dC-2- 3-Methylphenyl) -trifluoromethyl -amyooxazolin and its fumarate ,. ; . Stage A. 3-MethyltrifluoroacetopheNon. In a three-necked flask equipped with a stirrer and an inert gas inlet device, 4i g of m-bromotoluene and 300 ml of tetrahydrofuran are introduced. When dissolving, 5.85 g of magnesium chips and a few iodine crystals are added to the mixture to initiate a chemical reaction. This mixture is heated at boiling with uniform stirring. Heating is continued until the whole period is involved in the reaction, then the temperature of the mixture is set to normal and very quickly {solution of 6.16 ml of trifluoroacetic acid: Al6 in 15 ml of tetrahydrofuran is added. The introduction of this solution is continued for about 10 minutes, after which it is heated under reflux for 90 minutes. After that, sweep the ydydr in a calm state for 36 hours, and then pour it into the mixture consisting of water, ice and hydrochloric acid. The aqueous phase is extracted three times with isopropyl ether. The ether phases are separated, combined with each other, washed with water, then; saturated sodium bicarbonate solution and then again with water until neutral wash water. -V Reitv br vysuShvadt Haff sul sodium, then evaporated to dryness. Dried residual product of purification by fractional distillation and reduced pressure. Collect a fraction that distilled off PGI temperatures in the range from 60 to at a pressure of 3 mm Hg. Repeatedly separates the pure fraction.
12
725561 dispersed at temperatures in the interval from 80 to (35 mm Hg). The yield of 9.1 g (60%). Stage B. (3-Methylphenyl) -trifluoromethyl ketoxime. 7.5 g of trifluoroacetophenone and 4.7 g of hydroxylamine hydrochloride in the presence of sodium acetate are used as starting products of the reaction; 4.75 g of the corresponding oxime is obtained. After recrystallization from cyclohexane, m.p. 6365 0. Stage B. SZe-Z-Methylphenyl-c-trnfluoroethylamy. BocctaHOBJieFiHo 4 g of (3-methylphenyl) trifluoromethyl ketoxime, taken in an amount of 4 g; alum- lithium hydride in a solution of ether leads to the formation of 2.8 g of a racemic mixture of optical isomers (3-methylphenip) -trifluoroethyl, Step G. d € - s.-Trifluoroethyl) - (3-methylphenyl) -N (((. l-chloroethyl) urea. As starting materials, 4.2 g of a racemic mixture of (3-methylphenyl) -ct-trifluoroethylamine isomers and 2.8 g of isocyanate f-chloroethyl are used, and the reaction is carried out in the presence of 0.7 g-o : triethylamine, whereby N- (cC-trifluoroethyl) - (3-meth, ylphenyl) -N- (y-chloroethyl) -urea is obtained in a yield of 78%. Step D. dC-2 (3-Methylphenyl) -c, ..- trifluoroethyl aminoox Azoline. Using 7.6 g of NW-trifluorostil) - (3-methylphenyl) -N - (p-chloroethyl)-urea as the starting material in a suspension consisting of 75 ml of water and 4.5 ml of triethylamine, 5 are obtained, 41 g of d6-2- (3-methylphenyl) -oL, dL-trifluoroethyl 1-aminooxazoline as an oily product, soluble in most common organic solvents and in dilute solutions of mineral acids. Herd E. Preparation of fumaric acid salt. 2- (3-Methylphenyl), od, ob- (trifluoroethyl) -amino-oxazoline in the amount of 2.53 g is dissolved in 15 ml of ether. A solution of 0.75 g of fumaric acid in 12 ml of ether is very quickly added to the resulting solution. Crystallization of the fumarate is initiated by mechanical stirring and the mixture is kept at rest under ice-cooling conditions overnight. Next, the crystals formed are separated by filtration, washed, washed with a minimum amount of ether and dried under vacuum. Thus, 1.16 g of the fumaric acid salt are obtained as colorless crystals; m.p. 135-137 s. For the analysis of this fumaric acid salt, it is recrystallized from acetonitrile. Temperature of the crystallized product board 138.

权利要求:
Claims (1)
[1]
1. Weigand-Hilgetag. Methods of experiment in organic chemistry, M.,
 "
eleven
Chem
1968, p. 377.

类似技术:

---

公开号 | 公开日 | 专利标题

---

SU725561A3|1980-03-30|Method of preparing aryltrifluoroethylamines or their salts or their optical isomers or mixtures of their optical isomers

---

JP4279903B2|2009-06-17|Novel intermediates and methods for their preparation

---

US5922864A|1999-07-13|Efficient synthesis of a 1,4-dihydro2H-3,1-benzoxazin-2-one

---

SU664564A3|1979-05-25|Method of obtaining phenylpiperazine derivatives or salts thereof

---

EA014559B1|2010-12-30|A method for the preparation of |-n-methyl-3-|-3-|propylamine hydrochloride |

---

SU602112A3|1978-04-05|Method of producing amines, their salts, racemates or optically-active antipodes

---

KR860000063B1|1986-02-06|Process for preparing a furan derivative

---

CN112272665A|2021-01-26|Process for preparing sitagliptin

---

US4347374A|1982-08-31|Acid addition salts of N-trityl-α-fluoromethylhistidine enantiomer derivatives

---

KR100399854B1|2003-12-18|An Arthropodicidal Oxadiazine Intermediate

---

KR19980081393A|1998-11-25|Method for preparing chloroketoamine using carbamate

---

KR860000767B1|1986-06-23|Process for preparing nizatidine

---

SU633481A3|1978-11-15|Method of obtaining 2-thienyl-| ketone

---

SU927113A3|1982-05-07|Process for producing pyridylamine derivatives

---

Blomquist et al.1934|The Preparation and Reactions of Some Furyl Isocyanates

---

SU220979A1|

---

SU650502A3|1979-02-28|Method of obtaining 4-|-benzylnicotinate or salts thereof

---

US2899429A|1959-08-11|Nitroethylenes

---

SU156542A1|

---

US4125728A|1978-11-14|Method for preparing 2,3,7,8-tetraazaspiro[4,4]nona-2,7-diene

---

SU178816A1|METHOD OF OBTAINING NITROBENZOIC ACIDS

---

SU110906A1|1956-11-30|The method of obtaining nitroacetophenone

---

US4587344A|1986-05-06|Isothiourea synthesis process

---

KR810001915B1|1981-11-27|Process for preparing amino alkyl furan deriatives

---

KR870001001B1|1987-05-18|Process for the preparation of aminomethyl furan derivatives

同族专利:

---

公开号 | 公开日

---

US4267345A|1981-05-12|

---

US4315019A|1982-02-09|

---

US4315020A|1982-02-09|

---

IL52137A|1982-01-31|

---

PT66584B|1978-10-20|

---

NL169182B|1982-01-18|

---

GR61659B|1978-12-05|

---

FR2358890B1|1978-12-15|

---

DE2723464A1|1977-12-08|

---

AU517715B2|1981-08-20|

---

CH625795A5|1981-10-15|

---

HU177039B|1981-06-28|

---

BE854908A|1977-11-23|

---

NL169182C|1982-06-16|

---

OA05668A|1981-05-31|

---

PH13880A|1980-10-24|

---

GB1564268A|1980-04-02|

---

JPS5325565A|1978-03-09|

---

AU2537677A|1978-11-30|

---

IL52137D0|1977-07-31|

---

JPS584715B2|1983-01-27|

---

NZ184175A|1979-07-11|

---

AR219296A1|1980-08-15|

---

PT66584A|1977-06-01|

---

JPS55127390A|1980-10-02|

---

GB1564269A|1980-04-02|

---

ES459086A1|1978-04-16|

---

SU791234A3|1980-12-23|

---

DE2723464C2|1983-08-11|

---

FR2358890A1|1978-02-17|

---

ATA368277A|1978-10-15|

---

AT350062B|1979-05-10|

---

SE7705986L|1977-11-25|

---

AR222022A1|1981-04-15|

---

NL7705727A|1977-11-28|

引用文献:

---

公开号 | 申请日 | 公开日 | 申请人 | 专利标题

---

---

US2889351A|1956-05-25|1959-06-02|Pfizer & Co C|Therapeutic agents|

---

US3626067A|1965-07-01|1971-12-07|Du Pont|Substituted oxazolines, useful as pharmaceuticals|

---

US3453284A|1966-01-19|1969-07-01|Du Pont|Certain 2--2-oxazolines|

---

DE1670751A1|1966-09-27|1970-12-23|Bayer Ag|Process for the preparation of 2-phenylamino-2-oxazolines|

---

US3622067A|1969-06-13|1971-11-23|Ok Partnership Ltd|Document coder|

---

BE754832A|1969-08-14|1971-02-15|Beecham Group Ltd|IMINAZOLINES|

---

USRE27133E|1970-03-20|1971-06-01|Cdj)zco |

---

GB1453703A|1972-12-28|1976-10-27|Science Union & Cie|Substituted cyclopropylmethylamines processes for their preparation and pharmaceutical compositions containing them|

---

US4102890A|1972-12-28|1978-07-25|Science-Union Et Cie, Societe Francaise De Recherche Medicale|2-Amino oxazolines and process for making the same|

---

FR2269341B1|1974-04-30|1978-07-28|Castaigne Sa|

---

GB1475513A|1974-06-20|1977-06-01|Science Union & Cie|Benzylamine derivatives process for science union et cie benzylamine derivatives process for their production and pharmaceutical compositions containing them|FR2444673B1|1978-12-20|1981-04-17|Science Union & Cie|

---

US4348247A|1979-02-26|1982-09-07|Rockwell International Corporation|Method of fabricating a reinforced tubular structure|

---

EP0141686B1|1983-08-11|1987-09-09|Synthelabo|Indole derivatives, their preparation and their therapeutical application|

---

JPH06312412A|1992-06-10|1994-11-08|Nippon Hume Pipe Co Ltd|Composite concrete product with pattern, and its forming|

---

AUPP020297A0|1997-11-05|1997-11-27|University Of Melbourne, The|A novel receptor, and compounds which bind thereto|

---

JP2004534014A|2001-04-16|2004-11-11|ユニバーシティオブバージニアパテントファウンデーション|New oral general anesthetics and metabolic resistant anticonvulsants|

---

EP2070923A1|2007-12-11|2009-06-17|Bayer CropScience AG|Insecticide iminoheterocycles|

---

UY32940A|2009-10-27|2011-05-31|Bayer Cropscience Ag|AMIDAS REPLACED WITH HALOGENO RENT AS INSECTICIDES AND ACARICIDES|

---

AR085509A1|2011-03-09|2013-10-09|Bayer Cropscience Ag|INDOL- AND BENCIMIDAZOLCARBOXAMIDS AS INSECTICIDES AND ACARICIDES|

---

WO2014026984A1|2012-08-17|2014-02-20|Bayer Cropscience Ag|Azaindole carboxylic acid amides and azaindole thiocarboxylic acid amides for use as insecticides and acaricides|

法律状态:

优先权:

---

申请号 | 申请日 | 专利标题

---

FR7615601A|FR2358890B1|1976-05-24|1976-05-24|

---