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    • 专利摘要:
    METHOD FOR OBTAINING DERIVATIVES 2- (TIENSH1-2) - OR 2- (THIENYL-3) THIS PASSAGE OF GENERAL FORMULA (1) Ri-FT-CH-CH-NH-dHj-Ar chyg: 1 I RZ Rj where R - hydrogen c: 1-4 carbon atoms; Rj is hydrogen shsh alkyl with 1-4 carbon atoms; RJ is hydrogen or phenyl; Ar - thienyl, furyl, oiridyl or unsubstituted phenyl substituted by halogen or nitro, characterized in that in order to simplify the process, the compound of the general formula (II) is P - CH - NHg gH R. Where RJ - has the indicated values; X and Y are the same or different alkoxy with 1g-4 carbon atoms or phenyl. with the aldehyde of the total LCHO, where Ar has the indicated values, the obtained derivative of the general formula (IV) (iH-Ar. Y Kz, where X, At the Ar and R have the specified values, is treated with alkali B® M® at room temperature, the resulting carbonion of the formula (V ) X. P-CH-H CH-AG O) Y o k. Where X, Y, R and Ar have the indicated meanings; M® is an alkali metal cation, reacted in toluene 4 With a compound of the general formula (VI) 00 O) with where R and Rg have the indicated meanings, the resulting compound of the general formula (Vli) ci-N (iH-Ar R, 3 where R-Rj and Ar have the indicated meanings, are reduced with sodium borohydride in dioxane or ethanol.
    公开号:SU1148563A3
    申请号:SU823459385
    申请日:1982-06-29
    公开日:1985-03-30
    发明作者:Шекрун Исаак；Эймес Ален
    申请人:Санофи (Фирма)；
    IPC主号:
    专利说明:

    1 The invention relates to a new method of 2- (thienyl) ethylamine derivatives, which are used in the synthesis of biologically active substances. One method is known for the preparation of 2- (thienyl-2) - or 2- (thienyl-3) derivatives of ethyamine, which consists of such that thiophene is treated with n-butyl lithium, the resulting compound is treated with ethylene oxide or its derivative. As a result of the reaction of the corresponding 2-hydroxyethylthiophene derivative with an aryl or alkyl sulfohalogenide, an ether is obtained, which is aminated with the corresponding arylamine D 3. The disadvantage of this spxg: both are explosive and laboriously used butyl lithium. The purpose of the invention is to simplify the method. This goal is achieved by the fact that according to the method of producing 2- (thienyl-2) - or 2- (thienyl-3 ethylamine derivatives of the general formula Ri-TT-CH-CH-NH-CHg-- P f Kg Kz where R: - hydrogen or alkoxy with carbon atoms; 1-4 atoms hydrogen or alkyl with carbon mothers; hydrogen or phenyl; thienyl, pyridyl furid, or phenyl unsubstituted or substituted by halogen or nitro, the compound of general formula pn-sh2; i.3 has the indicated the values of X and Y are the same or different alkoxy with 1-4 carbon atoms or phenyl, condense with the aldehyde of the general formula These values, the derived derivative of the general formula - C-CH-AgC R, have the indicated 3 are treated with alkali ® at room temperature, the resulting carbonion of the formula p-C N-dH-Ar where X, Y, Rj and Ar have the indicated values; - cation alkali metal; is reacted in toluene with a compound of the general formula where R and R have the indicated meanings, the resulting compound of the general formula "-c jC-N C H-Ar R, i j.3 where RjH Ar have the indicated meanings, restore sodium borohydride in dioxane or ethanol. The proposed method can be carried out as follows. The organophosphorus compounds of the formula (II), which are easily obtained in a known manner, can be reacted with carbonyl derivatives (III) in the absence of a solvent and a catalyst, the water formed during the reaction being removed. termination of the operation in appropriate ways. The condensation can be carried out in a solvent such as an aromatic hydrocarbon, e.g. toluene, or an alcohol, e.g. ethanol, from which water is removed by azeotropic distillation. Condensation can be carried out in the presence of catalytic amounts of an inorganic IP organic acid (for example, g-toluenesulfonic acid). The transformation temperature is 20-120 ° C. Usually, the base BM is used in a slight excess, for example, 10% with respect to the stoichiometric equivalent. Example 1. Obtaining the hydrochloride of H-o-chlorobenzyl-2- (thienyl-2) ethylamine. Stage. " (Diethyl-H-O-chlorobenzylidene) α-1 nomethylphosphone 1. To 16.7 g (0.1 mol) of ethylaminomethyl phosphate in 200 MJJ of toluene, 14 g (0.1 mol) of 2-chlorobenzalde guide are added dropwise at room temperature. At the end of the addition of ir: the mixture is stirred for 30 minutes. The water formed during the reaction is removed by decantation. The toluene phase was washed with 50 ml of an aqueous saturated solution of sodium chloride, dried, taken up with sodium sulfate, then evaporated. Obtain 29 g, yield 100%, (di TI: -K 0 -chlorob ennpid en) aminometraphosphate in the form of a yellow oil, giving one fifth with those silica gel, ethyl acetate, Rf 0.45 eluent. IR (film), 1635; 1250; 1060 - 1030 sk. NMR spectrum (CJXC, cL) TMS: 1.35 m. : (trishet, 6H); 4.2 ppm (multiplet 6H); - 7.5 ppm, (multiyipet, EIT 8 ppm (multiplet, 1H); 8.7 ppm, (doublet, 1H). Step 6. 1 -2-Chloride) -4- (tiie nyl-2) -2-azabutyene-1,3. To a vigorously stirred mixture of a 50% aqueous solution of sodium hydroxide and 80 ml of toluene were added 1.47 g (4 mol) of tetra-c-butylammoium iodide, then a solution of 28.95 g (0.1 mol) was added dropwise. of the obtained amine and 11.2 g (0.1 mol) of 2-tnaldehyde 9 20 ml of toluene. At the end of the addition, during which the temperature rises from 20 to, the reaction mixture is brought to constant with 30 minutes under stirring. After cooling and separation of the phases by decantation, the aqueous aqueous phase is extracted twice with 50 ml of toluene. The combined sfga and the organic phases are washed with water, dried with sodium sulfate, then evaporated. 19.8 g (yield 80%) of 1-C2-hl0rf € Nile) 4- (thienyl-2) -2-azabutadiene-1,3 are obtained in a yellow yellow oil, giving almost one spot in thin layer chromatography. IR spectrum (film): 1640 cm NMR (ODS1 j), 6 ppm (Sivglet, 1H); 8 ppm (multiplet, 1H); 6.9 - 7.9 ppm (multiplet, 8H). Stage in. N-o-chloro 5-diznes-2- (thieNiL-2) ethylamine hydrochloride. To a solution of 6.08 g (0.16 mol) of boron sodium hydroxide in 150 ml of ethanol is added dropwise over 5 minutes to the resulting cad azadiene (19.8 g) as a solution in 50 mp of ethanol. At the end of the addition, in which the temperature rises to 20-30 ° C, the reaction medium is slowly brought to 45-50 ° C and the mixture is kept at this temperature for one hour. Then the reaction mixture was evaporated and the resulting residue was treated with diisopropyl ether. The ether phase is washed several times with 1N. sodium hydroxide solution, water is dried with sodium sulfate, then evaporated. 20 g (yield 100%) of H-o-chlorobenzip-2- (thienyl-2) ethylamine are obtained in the form of a light yellow oil. To the obtained crude base, suspended in 50 ml of water, is added dropwise at 50 ° C 8.3 mp 12 n. hydrochloric acid, then the mixture is adjusted to. The resulting homogeneous solution is cooled, crystals are formed, which are filtered, washed with water, then dried in vacuo at. 20.4 g (71% yield relative to the diethylaminomethylphosphonate used in stage a) of H-0-chlorobenzyl-2 (thienyl2) ethylamine in vvde white crystals are obtained. M.p. . IR spectrum (tablets with KBV): 3400, 2900-2600, 1575, 1450 cm. NMR (DMSO d (,, c) TMS: 7-7.8 ppm (multiplet, 8H); 3.35 ppm (singlet, 4H); 4.15 ppm (singlet, 2H ); 9 ppm (multiplet, 2H) exchanged with. Calculated,%: C 54.16; H 5.24; N 4.85. C jH ClNS-HCl Found,%: C 54.07; H 5.31; N 4.80. Example 2. Preparation of M-o-chlorobenzyl-2-thienyl-3) ethylamine hydrochloride. Stage. " Dienyl-H-o-chlorobenzylidene aminomethylphosphonate. According to the method of example 1 and using the same amounts, get 29 g (yield 100Z) of the specified product. Step 5. 1- (2-Chlorophenyl) -4- (thienyl-3) -2-azabutadiene-1,3. Analogously to Example 1, but using 3-thienaldehyde, 19.6 g (yield 79%) of 2-azabutadiene-1.3 is obtained as a yellow oil, which is reacted without purification. Stage in. N-0-chlorobenzu1-2- (thienyl-3) ethylamine hydrochloride. Following the metric test of example 1 and using the product obtained on the previous hundred $ 11 days, 19.2 g are obtained (yield 66% calculated on the product used in step o (diethylamidomethylphosphonate) in the form of white crystals. Mp. NMR (DMSO dt,) TMS: 3.2 ppm (singlet, 4H); 4.05 ppm (singlet. 2H); 9 ppm (multiplet, 2H) exchanged with fljO; 6.9-7, 8 ppm {muplet, 7H). IR spectrum (tablets with KBV): 3400, 2900, 2700-2800, 1575, 1450 cm-. Calculated,%: C 54.16; H 5.24; N4.85. C H CINS-HCI Left,%: C 54.13; H 5.30; N 4.82. Example 3. Chlorohydrate of N- (thienyl-2) -methyl-2- (thienyl-2) ethylamine. Stage. " Diethyl-K-thienylidene nomethylphosphonate. A solution of 16.7 g (0.1 mol) of diethylaminomethylphosphonate in 200 ml of absolute ethanol was added to 11.2 g (0.1 mol) of 2-thienaldehyde, and the mixture was heated under reflux. then evaporated, to obtain 26 g of diethyl-H-2thienylidene aminomethylphosphonate (yield about 100%) as a yellow oil, giving one spot when analyzed using those (silica gel, ethyl acetate as eluent). IR (film): 1640; 1260; Р-О-С 1060-1080 cm. NMR (CDC1e, cL) TMS: 1.35 ppm (triplet, 6H); 3.9-4.45 ppm (multi plet, 6H); 7-7.7.8 ppm (multiplet, SN); 8.5 ppm (doublet, 1H). Stage b. 1- (Thienyl-2) -4- (thienyl 2) -2-azabutadiene-1,3. Following the procedure of Example 1, 18.6 g (85% yield) of the indicated 2-azabutadiene-1.3 are obtained as yellow crystals. M.p. 163 C. IR spectrum (tablet with KBr) 1635 cm-. NMR spectrum (DMSO dt): 8.35 ppm (singlet, 1H); 6.9 7.5 ppm (multiplet, 8H). Calculated,%: C 60.27; H 4.10; N 6.39. Found,%: C 60.25; N. 4.07; N 6.40. Stage 6. Hydrochloride N- (thienyl-2) methyl-2- (thienyl-2) ethylamine. To 10.95 g (0.05 mol) of the obtained 2-azadiene-1,3, suspended in 100 ml of ethanol, 3.7 g per 36 (0.1 mol) of sodium borohydride are added, then the reaction mixture is heated to 4045 ° s After stirring for two hours at this temperature, the mixture becomes homogeneous and colorless. Next, the mixture is treated as in Example 1. The resulting crude base, dissolved in diisopropyl ether, is added to a 4.5 N solution of hydrogen chloride in the same solvent. The precipitate formed is filtered off using di-isoproxy ether and then dried at 50 ° C under vacuum. This gives 11.15 g (yield: 73%, based on diethypaminomethylphosphonate) hporghydrate H - {; thienyl-2) -methyl-2- (thienyl-2) ethnpamine in the form of white crystals. T.SH1. (dilution). IR spectrum (tablet with KBG): 3400, 2920, 2750, 1440, 1250. NMR (DMSO d): 6.9 - 7.5 ppm (multiplet, 6H); 4.40 ppm (singlet 2H); 3.2 M.D. (multiplet 4H); 9 ppm multiset 2H), obmeinvayuyu on D20. Calculated,% C 50.86; H 5.39; N 5.39. C., Hi, NS2HCl Found,%. C 50.90; H 5.40; N 5.37. PRI me R 4. N-0-Chlorobenzyl 5-tert-butoxy (thienyl-2) 1 ethylamine Step a. Diethyl-H-o-chlorobenepipylamine-methylphosphonate. They work with the same amounts of the ® conditions as in example 1. Stage 6. 1- (2-Hpriphenyl) -4 5-tert-butoxy (Tien-1-2) -2-azabutadien-1, 3. To a solution of 0.1 mol of imine imine in 100 ml of anhydrous tetrahydrofuran (THF), under a nitrogen atmosphere, was added a 2.8 M (0.1 mol) solution of n-butyl lithium in hexane. The resulting dark red solution is kept under stirring at a temperature and under nitrogen atmosphere for 30 minutes, then a solution of 18.4 g (O, T mol) of 5-tert-butoxy-2-thienapdehyde in 20 ml is added under the same conditions. anhydrous THF. After the addition is complete, the yellow solution is stirred at room temperature for one hour, then evaporated in vacuo. The residue after treatment with water is extracted with two radioisopropyl ether. The combined organic phases, dried with sodium sulfate, are evaporated in vacuo to give 32 g of 1- (2-chlorophenyl) -4C5-tert-butoxy (thiennl-2) 3-2-a9buta diene-1.3 c. Yellow oil used further without purification. . Stage in. MO-ZeLerLenzyl-2-C5 tert-butoxy (tyllig23 ethylam1 a. From 16 g (0.05 mol) of semi-eno 2-azabutadiene-1.3 and 3.8 g (0.1 mol borohydride sodium, work on gfimer7 1, get 13 g of the ammunition in the form of a yellow oil, which is i.e., pymevedex yen and oxalate. 2) J etadamine Bi in the form of light yellow color, Hrae oxalate reduction. IR spectrum (film); 3800, 28503000, 1569, 1150 EMU. NMR (CflClj) base (c) –ShS: 1.3 m, D (singlet, 9H); (CHj) j With 1/7 MD (singlet, 1H), exchanged with DGO} 2.8 m. . (singlet, 4H) TsAnsHg-SNg-K 5.85 ppm (singlet I 2H) -N-CHj-Ar 6.05 MD (dubet, 1H) | H | / - and C 6, 35 KD (doublet, 1H)) te AB from 7.2 ppm (multiplet, 4H). Calculated,%: C 55.13; H 5.84; N3.39. C 7Z2aNC10S-C2H204: C 55.02; H 5.87. Found N 3.37. PRI me R 5. Obtaining the hydrochloride To-o-chlorobenzyl-2-methyl-2- (tnenil-2) ethylamine. Stage SI. Diethyl-M-chlorobenzylidene aminomethylphosphonate. Following the procedure of Example 1, 0.088 mol of the indicated imine is obtained. . Stage 6. 1- (2-X o1) phenyl) -4- (thieHN1-2) -4-methyl-2-azabutadiene-1,3. 23.4 ml of a 252% solution of n-butyl lithium in hexane (0.088 cools) is added to the obtained i.e. (0.088 mol) in 100 ml of anhydrous THF. g (0.088 mol) of 2-acetylthiophene and 20 ml of THF. The reaction medium was boiled for 2 hours and then 12 hours at room temperature, poured into a saturated aqueous solution of ammonium chloride and finally extracted with three MP of methylene chloride. The combined organic phases washed with water, dried sodium sulfate, after evaporation give oil a clear residue that hardens when ground with diisopropyl ether. 14.6 g is obtained (yield 63%) of 1- (2-chlorophenyl) 4- (thienyl-2) -4-methyl-2-azabutadien-1, 3 as yellow crystals, giving one spot at tech. Thus, IR spectrum (tablet with KBr): 30 2940, 1620, 1580, 1540, 1465 ,. 1435 cm-. NMR spectrum (SDC1, SLUTMS: 2, 2 dm (singlet, ZN); 6.9–8.1 ppm (multiplet, VN); 8.75 ppm (doublet, 1H). Stage in. Chlorine hydrate L – o zsorbenzyl-2-methyl-2- (thienyl-2) ethnlamine. From 1 g of the 2-azabutadiene-1, 3 obtained, p1 working in the same way as the previous examples, 0.8 g (70% yield per azadiene) of the indicated hydrochloride is obtained in the form of white crystals. M.p. . IR spectrum (tablet with KBV): 3400, 3000-2800, 1570, 1460. NMR spectrum (DMSO d, /) TMS: 1.32 ppm (doublet, SN); 3.05 ppm (doublet, 2H); 3.45 ppm (multiplet, 1H) | 4.1 ppm (singlet, 2H); 6.957, 6 ppm (multiplet, 7H); 9 ppm (multiplet, 2H), exchanged with D20. PRI me R 6. Hydrochloride N-ehlorbenzyl-1-phenyl-2- (thienyl-2) ethylamine. Stage and. Diethyl-N-O-chlorobenzylidene-y-phenylaminomethylphosphonate. Work according to Example 3, out of 12.15 g (0.005 mol) of diztil-cC-phenylaminomethylphosphonate and 7.02 g (0.05 mol) of o-chlorobenzaldehyde, 18.8 g (yield 100%) of the indicated product are obtained in the form of light Kelto oil, giving one spot at TLC. IR spectrum (film):, 1635, 1250, 1080-1050, 970cm-. NMR spectrum (CDS, l) TMS: 1.2 ppm (triplet, 6H); 3.9 ppm (muYa, 4R); 4.8 ppm (doublet, 1H); 7-7.8 m "d. (multiplet, 8H); 8.1 ppm (multippet, W); 8.65 ppm (doublet, 1H). Step 5. 1- (2-Chlrrphenyl) -3-fennl4- (thienyl-2) -2-azabutadiene-1,3.
    To 3.65 g (0.01 mol) of the obtained imine in 50 MP of anhydrous THF, with stirring and in the nitrogen atmosphere, add 3.6 ml (O, It mol) of a 2.8 M solution of m-butyl lithium in hexane. After further stirring for 30 minutes, a solution of 1.12 g (0.01 mol of 2-thienaldehyde in 20 ml of THF) is added (at 78 ° C). The reaction mixture is then stirred for 2 hours at room temperature, then evaporated. The residue is treated with a mixture of water and chloroform. The separated organic phase, washed rfie several times with water, dried with sodium sulfate, after evaporation gives an oil, which solidifies on trituration with methanol. 1.68 g (yield 52%) of the indicated 2-azabutadiene-1, 3 is obtained in the form of yellow crystals. mp. 118e.
    IR spectrum (tablet with KBV): 30003100, 1620, 1470-1440, 1265 cm.
    NMR spectrum (CDCS, L TMS: 8.85 md (singlet, 1H); 6.95-8.1 ppm (multiplet, 13H).
    Stage 8, M-o-chlorobenzyl-1-phenes-1-2- (thienyl-2) ethtamine hydrochloride.
    With a stirring, 0.57 g (0.015 mol) of sodium borohydride is added to a solution of 1 g (0.008 mol) of the obtained 2-azabutadiene-1,3 in 20 MP dioxane, the suspension is cooled to OC, then at this temperature is added dropwise 1 , 15 mp (0.015 mol) of trifluoroacetic acid. The reaction medium is heated under reflux for 2 hours. After the mixture becomes homogeneous, it is cooled, poured into water, then extruded with chloroform. The separated organic phase, washed several times with water, dried with sodium sulphate, after evaporation gives a pale yellow oil, which is treated with chloride. hydrogen in ethanol is converted to 0.58 g (52% yield based on azadiene) of N-0chlorobenzyl-1-phenyl-2- (thienyl-2) ethylamine hydrochloride in the form of white crystals. m.p. 214 €.
    IR spectrum (tablet with KBG): 3400, 2950-2700, 1565-1450 cm-1.
    NMR spectrum (DMSO d4): 3.1 ppm (doublet, 2H); 4.95 ppm (doublet, 1H) 4.2 ppm (singlet 2H); ; 6.9-7.95 ppm (multitshet, 12H), ppm (multiplet, 2H), exchanged with DGO.
    Example 7: Oxalate 2-N-Fyfryryl-2- (thienyl-2) ethylamine.
    Stage P. (Diethyl-2-H-furfurylidene aminomethyl phosphonate.
    Get 0.1 mol of the specified product (in the form of the same oil), work analogously to example 1.
    IR (film): 1645, 1250, 1060, 1050 cm-.
    NMR spectrum (SDS1, eL) TIS: 1.3 ppm (triplet, 8H); 4 ppm (multiplet, 6H); 7-7.5 ppm (multiplet, SN); 8.3 ppm (doublet, 1H).
    Stage S. 1- (2-Fourche1) -4- (Tiensh12) -2-azabutadiene-1,3.
    To a solution of 0.1 mol of the obtained imine in anhydrous THF is added dropwise under a nitrogen atmosphere and a 2.8 M solution (O, t mol) of n-butyl lithium in hexane. The solution is kept under stirring under nitrogen and under nitrogen for 30 minutes, then a solution of 11.2 g (0.1 mol) of 2-thienaldehyde in 20 ml of anhydrous THF is added under the same conditions.
    After the addition is complete, the solution is stirred at room temperature for 1 hour, then evaporated in vacuo. The residue after treatment with water is extracted with diisopropyl ether. The combined (sodium sulfate-rich pus and organic phases evaporated in vacuo give 22 g of 1- (2-furyl) A- (tyie1 "t-2) -2-azabutadiene-1,3" as a yellow oil, used without purification in the next stage .
    Stage 6. Oxalate 2-H- furfuryl-2 (thienyl-2) ztilamine.
    From the resulting azadiene and 7.6 g (0.2 mol) of sodium borohydride and operation as in Example 1, the indicated amine is obtained (as a yellow oil), which is purified by water in oxalate.
    17.3 g (58% yield, calculated on diethylaminomethylphosphate, onat) oxalate of 11- (2furfuryl) -2- (thienyl-2) ethylamine are obtained in the form of crystals. M.p. 215C.
    IR spectrum (tablet with KBG): 3400, 3040, 2850, 1715, 1650, 1480 cm.
    NMR spectrum (SDS1) base (/) 1.65 ppm (singlet, 1H), exchanged with DGO;
    2.8 ppm (singlet, 4H) CHz-CH
    3.65 ppm (singlet, 2H) | |
    .-CHg-N;
    0 6.1 ppm (multiplet, 2H); 6.67, 3 ppm (multiplet, an). Calculated,%: C 52.52; H 5.05; N 4.71. C. Found,%: C 52.50; H 5.03; N 4.65. Example 8-N- (Pikalil-4) -2 (thienyl-2) ethylamine. Stage o. Ionropshmino-4-pyridylcarboxaldehyde aminomethylphenylphosphinate. 0.1 mol of the above product is obtained (as a yellow oil), the work is carried out analogously to Example 1. IR spectrum (film): 3000, 1630, 1600, 1200, 980 cm; . NMR spectrum (CDC1) TMS: 1.4 m (double doublet, 6H); 4.15 ppm (two years old, 2H); 4.7 ppm (multiplet, 1H) 7-7.8 ppm (multiplet, 7H); 8.25 m (doublet, 1H); 8.55 ppm (doublet, 2H Stage 5. 1- (4-Pyridyl) -4- (thienyl-2) -2-azabutadiene-1,3. Work as in Example 7, get 18.2 g (yield 85.3%) azadiene in the form of an orange oil, which is used without purification in the next stage. Stage B. H- (Picolyl-4) -2- (thienyl-2) etipamine. From the resulting azadiene and 7.6 g (O, 2 mol) of borgndride sodium, work of example 1, gives the indicated amine as a light brown oil which is purified by column chromatography on silica gel, 9.17 g (yield 42% calculated for aminomethylphosphinate) H- (4-coli) -2- (thienyl -2) ethylamine in the form of slightly tinted m IR spectrum (film): 3300, 2900, 1600, 1440 cm-. NMR spectrum (CflClj, SL) TMS: 1.7 m (singlet, 1H) exchanged with, 3 ppm (triplet , 4H), Ar — CH —CHj), 3.8 ppm (singlet, 2H); Ar-CHj-N, 6.6 - 7.4 ppm (multiplet, 5H); 8.4 ppm (doublet, 2H). PRI me R 9. N-rOnitrobenzyl-2- (thienyl-2) ethylamine hydrochloride. Stage. " Isopropyl-11-0-nitrobenzylidene aminomethylphenylphosphinate. From 0.1 mol of o-nitrobenzaldehyde and 0.1 mol of isopropylaminomethylphenyl phosphinate receive (work analogously to example 1) 0.1 mol of the indicated imine as a yellow oil. 1 3 IR spectrum (film): 1680, 1200, 1980 cm-. H14 spectrum (SDS1): 1.5 ppm (doublet, 6H); 4.25 ppm, (doublet, 1H); 7.5-8.3 ppm (multiplet, 9H); 8.6 ppm (doublet, 1H). Stage 6. 1-about-Nitrophenyl-4- (ties-2) -2-azabutadiene-1, 3. From 0.1 mol of the obtained imine and 0.1 mol of 2-thienaldehyde, work according to Example 3, 22 g of azadiene are obtained (yield 85% based on aminomethylphosphinate) in the form of an oil, which is used without purification in the next stage. Stage in. Chlorine Nro-nitrobenzyl-2- (thienyl-2) ethnpamine hydrate. To the obtained azadiene in 200 ml of ethanol, 6.46 g (0.17 mol) of sodium borohydride are added in small portions, maintaining the temperature below 25 ° C. Then the reaction mixture is stirred for 2 hours at room temperature, 1 l of water is drunk and extracted with chloroform. Washed with water, dried with sodium sulfate and then one stripped of the organic phase gives the base in the form of an oil, which is converted to the hydrochloride by passing hydrogen chloride into an ethanol solution of this oil. After recrystallization, 18.2 g (yield 61% based on aminomethylphosphinate) of hydrochloride N-onitrobenzyl-2- (thienyl-2) ethylamine are obtained in the form of white crystals. T “SH1. 168C. IR spectrum (tablet with KBG): 3450, 3000, 2900, 2700, 1560, 1525, 1340 CM-V. NMR spectrum (VTS) base. (c) TMN: 1.65 ppm (singlet. 1H). exchanged with, 2.9 ppm. (triplet, 4H); 4 ppm (singlet, 2H); 6.7-7.9 ppm (multiplet, 7H). 1st, 1th,%: C 52.26; H 5.06; N 9.38. C jH NjOiS-HCl Navdeno,%: C 52, 28; H 5.03; N 9.31. Example 10. N hydrochloride chlorobenzyl-2- (tiensh 1-2) ethylamine. Stage a. N-0-chlorobenzylidene (aminomethylUdiphenylphosphine Oxide). To a solution of 3.5 g (0.015 moz) of aminomethyl / biphenylphosphine oxide in 150 MP, 2.18 g (0.015 mg) 1 dropwise at room temperature is added.
    OH chlorobenzaldehyde. After evaporation of the solvent by heating to 50 ° C under a slight vacuum, a light yellow oil is obtained, which is treated with a heated mixture (50 ml) of diisopropyl ether: and ethanol (2.5: 1), after cooling to 10c, filtered and dried under vacuum 4.9 g of crystal of the expected product are obtained. T.sht. .
    Stage 5. 1- (2-chlorophenyl-4-t-enyl-2) -2-azobadIo-1,3.
    To intensively mixed mixtures
    10 g of an aqueous 50% sodium hydroxide solution and 0.18 g of tetra-m-butylammonium iodide are added dropwise a solution of 2.65 g (0.0075 mol) of the resulting protein and 0.84 g (0.0075 mol) 2-thienaldehyde in 8 ml of toluene.
    Stirring is continued at room temperature for one hour. The toluene solution, separated after decantation, is washed with 50 ml of aqueous 2% sodium chloride solution, then evaporated in vacuo. The resulting oil, after treatment with 6 mp ethanol and cooling, is converted into JKu crystals, which are filtered and evaporated in vacuo at room temperature. Poluchgt 1.05 g of 1- (2-chloro; fluenyl) 4- (thienyl-2 -2-azabutadiene-1,3, mp. 65C.
    Stage 5. N-0-hlsrbenash1-2- (tieshsh-2) ethidamine hydrochloride.
    The procedure of Example 1 is followed, but starting from 0.45 g of the resulting aadiene and 0.2 g of sodium borohydride, 0.4 g of the expected product is obtained. M.p. 143C.
    权利要求:
    Claims (1)
    [1]
    METHOD FOR PRODUCING 2- (THienyl-2) -i or 2- (thienyl-3) ethylamine derivatives of the general formula (J)
    CH-CH-UN-CH g- Ag Λ K 2 K, where 1C - hydrogen or alkoxyl with
    1-4 carbon atoms;
    R 2 is hydrogen or alkyl with 1-4 carbon atoms;
    Rj is hydrogen or phenyl;
    Ar is thienyl, furyl, 'pyridyl, or phenyl unsubstituted or substituted by a halogen or nitro group, characterized in that, in order to simplify the process, the compound of general formula (II) ^ P-CH-HH / lg / · 1 Y 0 From where Rj - has the specified values;
    X and Ύ are the same or different alkoxyl with 1-4 carbon atoms or phenyl, condensed with an aldehyde of the general formula (III)
    AgSNO where Ag has * the indicated values, the obtained derivative of the general formula (IV)
    P-CH-N = Sn — Ag L I
    About R 3 where X, Y Ar and R have the indicated meanings, are treated with B® M ® alkali at room temperature, and the carbonion of the formula (V) is formed
    > R-Sn- -N = CH —Ag 1where X, Y, R and Ar have the indicated meanings;M® - alkali metal cation
    subjected to interaction in toluene with a compound of the general formula (VI) where R * and R 2 have the indicated meanings] the obtained compound of the general formula (VII)
    Ri- ^ JC = CN = CH- A r. β * g Kz where R t - Rj and Ar have the indicated meanings; they are reduced with sodium borohydride in dioxane or ethanol.
    „SU..1148563
    I
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    同族专利:
    公开号 | 公开日
    NO822224L|1983-01-03|
    CA1205810A|1986-06-10|
    US4482718A|1984-11-13|
    ZA824624B|1983-04-27|
    KR840000536A|1984-02-25|
    FR2508453A1|1982-12-31|
    PT75152B|1984-05-29|
    DK286682A|1982-12-31|
    EP0068978A1|1983-01-05|
    JPS5810574A|1983-01-21|
    AU566802B2|1987-10-29|
    NO155136C|1987-02-18|
    NO155136B|1986-11-10|
    CS248028B2|1987-01-15|
    DE3273015D1|1986-10-09|
    DD206377A5|1984-01-25|
    ES8305349A1|1983-04-01|
    IL65980D0|1982-09-30|
    HU194860B|1988-03-28|
    GR76496B|1984-08-10|
    FI822315A0|1982-06-29|
    IE53228B1|1988-09-14|
    AU8475582A|1983-01-06|
    AT21897T|1986-09-15|
    YU143382A|1984-12-31|
    EP0068978B1|1986-09-03|
    PT75152A|1982-07-01|
    FI822315L|1982-12-31|
    IE821310L|1982-12-30|
    NZ200852A|1985-09-13|
    IL65980A|1985-12-31|
    FR2508453B1|1983-12-23|
    ES514221A0|1983-04-01|
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    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    FR8113062A|FR2508453B1|1981-06-30|1981-06-30|
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