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    • 专利摘要:
    Optisch aktives Di-[3-chlor-2-oxy-propyltrimethylammonium]-tartrat.
    公开号:SU1491332A3
    申请号:SU864013918
    申请日:1986-01-29
    公开日:1989-06-30
    发明作者:Тенуд Леандер；Гостели Жак
    申请人:Лонца Аг (Фирма)；
    IPC主号:
    专利说明:

    The invention relates to an improved method for the preparation of an optically active carnitine nitrile chloride, a non-steroidal agent, which is used in pharmacology.
    The purpose of the invention is to simplify the process.
    The invention is illustrated by the following examples.
    Example 1. Getting) -3-chloro-2-hydroxy-propyltrimethylammo- (+) - tartrate.
    To 18.75 g (125 mmol) of L - (+) - tartaric acid, dissolved in 30 ml of water, 39 ml (259 mmol) of trimethylamine (45% in
    water), and the temperature is set at 30 ° C. The pH value of the solution is 7. Then the solution is cooled to 15. C and 23.15 g (250 mmol) of epichlorohydrin are added dropwise with stirring. The reaction temperature is maintained at and continued to stir the mass until the mixture obtained contains only the liquid phase.
    Upon completion of the reaction under vacuum (in a rotary evaporator) at 40 ° C evaporated water. 59.5 g of viscous oil are obtained.
    The residue is dissolved in 40 ml of hot methanol, after which 135 ml of acetone is slowly added until the solution is cloudy. The solution is defended for 3 days
    ;about
    oo
    00
    1C
     cm
    at room temperature, after which the mother liquor is cast, and the crystals are washed with acetone-methanol (4: 1) and extruded in vacuum. 4.75 g of lamellar crystals are obtained (yield 16.8% of theory). M.p. 150-1524. (oJlp -8, G (c - 1 in water).
    Example 2. Preparation of di- - (-) - 3-chloro-2-hydroxy-propyltrimethyl-ammoniumP-b - (+) - tartrate.
    150 g (1 mol) b - (+) - tartaric acid - 200 g mzzanol.
    weights are weighed in at 20 ° C over 10 hours. 106.2 (1.8 mol) of trimethylamine and 250 g of ethanol are added. The temperature is maintained at 20 ° C. The tartaric acid dissolves to form di-trimethyl ammonium b - (+) - tartrate. Then, 166.5 g (1.8 mol) of epichlorohydrin is added and the temperature is held at 20 ° C. Keeping this temperature, the mass is stirred for another 2 days. The precipitated crystals were filtered off, washed with acetone - methanol (4: 1) and dried in vacuum.
    The product (176.4) g, obtained with a yield of 38.9% (77.8%, from theory), has So pl. 157-158 p. ("1) -9.1 (s - 1 in water).
    Example 3. Obtaining (-) - 3-chloro-2-hydroxy-propyltrimethylammonium-chloride.
    To 18.35 g (40.5 mmol) of the tetrate of Example 1 in 65 ml of water, 4.50 g (40.5 mmol) of calcium chloride dissolved in 15 ml of water was added dropwise to the vessel. The tar of calcium is precipitated immediately in the form of crystals. After 5 minutes, the suspension is cooled in an ice bath (the solution has a pH value of 7), and the calcium tartrate is filtered under suction. After washing with methanol and drying in air, it weighs 10.08 g (theoretical theoretical weight is 10.54 g, yield 95.6%).
    The filtrate (and washing matanol) is evaporated on a rotary evaporator at a bath temperature of 50 ° C. Tver
    This residue weighs 17.0 g (15.24 g from theory). It is digested with 25 ml of absolute ethanol at 70 ° C. The suspension is cooled in an ice bath and the crystals are filtered under suction. After washing with ethanol - acetone (1: 1) and acetone, air drying is carried out. Output 10.24 g of colorless crystals (67.2% of theory), so pl.
    2144 .. (Y.} - -28.76 ° (s - 0.97 in water).
    Example 4. Obtaining (-) - glycidyltrimethylammonium chloride - (-) - N, N, N-trimethyl-oxycarbonyl-amine).
    To 9.5 g (50 mmol) of (-) - 3-chloro-2-hydroxy-propyltri1 ethylammonium chloride (99.1%), (S –29.5 C (s - 1, H, jO) , mp. 2 | 2-214 s), dissolved in 35 ml of methanol, a solution of 2.05 g of sodium hydroxide (98%, 50 mmol) in 45 of methanol is added dropwise with stirring. Then the resulting mixture is stirred for 3 h, then the precipitated sodium chloride is filtered
    0
    five
    0
    Q
    five
    0
    (2.6 g, 89%) and twice with 5 ml of methanol. Finally, the filtrate and the washing ethanol are evaporated.
    The crude product (8.95 g, 117%) is placed in 50 ml of chloroform, in which it gradually dissolves after shaking, with a small amount of undissolved NaCl remaining. Undissolved NaCl (0.60 g, 20%) is filtered off.
    After evaporation of the SNRC, 7.6 g (99.3% of (-) - glycidyltrimethyl-ammonium chloride) are obtained.
    The product does not contain the starting material (according to TLC). 121-125.5 ° C. (с) -27 °, О (с - 1 in water).
    IR (Ld): 3440s; 3030w, 2980w, 2940w; 1630m, - 1485s; 1420w; 1270w; 1150w; 1100w; 980m; 935s; 900m; 870m; 805w; 770w.
     H-NMR (300 MHz, d DMCO):
    2, .69 (dd, 1H, and 3 Hz, H – C (3),
    2.93 (dd, 1H, and 5 Hz, H – C (H),
    3.22 (dd, 1H, and 8 Hz, H – C (1),
    3.23 (s, 9H, -N (CH,),),
    3.57 (dddd, 1H, (5) 3 and 3 Hz,
    HC (2),
    4.04 (dd, 1H, iZ Hz, H – C (1).
    Example 5. Preparation of (-) - glycidyltrimethylammonium chloride ((-) - —Y, S, N-trimethyl oxyranmethanamine).
    K 9.5 g (50 mmol) of (-) - 3-chloro-2-oxy-propyl trimethylammonium chloride
    five
    (99.1%, W
    24
    -29.5 (s - UHjO),
    m.p. 212-214 C), dissolved in 35 MP of methanol, with stirring at room temperature, a solution of 5.8 g of KOtBu (97%, 50 mmol) in 20 ml of methanol is added dropwise. The mixture is stirred for 3 hours, precipitated iiii KC l (,) S r,) (filtered and washed twice with 3 ml of ethanol. The filtrate and the ethanol are then evaporated. The crude product (9.15 g, 119;) is mixed with 50 ml of chloroform. By shaking, the product can be gradually dissolved except for an insignificant amount (0.05 g) of insoluble KC1, which is separated by filtration.
    By evaporation of CHCl j, 7.5 g (98%) of (-) - glycidyl trimethylammonium chloride are obtained.
    The product according to TLC does not contain the source material. M.p. 119-121 ° C. (S) -27, G (s - 1 in water
    Example 6 Preparation of L-Carbonitrile Nitrile Chloride
    4.35 g of ac toncyanohydrin (98%, 50 mmol and 7, 9 g (50 mmol) of (-) - glycidyltrimethylammonium chloride) are added to 10 ml of MeOH. The mixture is stirred at 20-25 ° C until the components are completely dissolved. Then, the resulting solution is heated to 45 ° C for half an hour and continued to stir for 4 hours at the same temperature (checking the reaction on the basis of TLC data), and after half an hour at 50 C the target product begins to precipitate. The mixture is cooled to 20 C then formed white crystals are sucked off on a putsch, washed three times with ace oxazolidinone (6 ml) and finally they are dried.
    Output 7.5 g (81.6% of theory). M.p. 246 ° C (with decomp.). (oi) -25.6 ° (s - 1 in water).
    The resulting product, based on data from BLC, turns out to be 97.3% and contains another 2.4% (-) - glycidyltrimethyl ammonium chloride.
    As a result of recrystallization from ethanol (95%), long needles are obtained. M.p. -25,8
    Example 7. Obtaining di - (-) -3-chloro-2-hydroxy-propyltrimethylammo- (+) - tartrate.
    To 18.75 g (125 mmol) of L - (+) - tartaric acid, dissolved in 30 mp of water, 35.2 mp (250 mmol) of trimethylamine are added dropwise for 10 minutes, while the temperature is kept at. The pH value of the solution is 7. Then the solution is cooled to 20 ° C and with a displacement of 256 ° C (with decomp.). (o) J, (c - 1 in water).
    ten
    15
    20
    25
    thirty
    35
    40
    45
    50
    55
    1326
    23.15 i (250 mmol) -chpichlorg idrina is added dropwise by shivngTneum. After 14 hours at 60 ° C, 60 ml of isophopanol is added. The precipitated crystals are filtered, washed with acetone-methanol (4: 1) and dried in vacuo.
    The product (16.3 g) obtained with BbixojioM 28.8% (57.6% of theor.), Has So pl. 152-154 p. ((x) p -9.6 (s - 1 in water).
    Example 8. Obtaining di - (-) - -3-chloro-2-hydroxy-propyltrimethylammonium-L - (+) - tartrate.
    To 18.75 g (125 mmol) of L - (+) - tartaric acid, dissolved in 10 ml of water and 60 ml of isopropanol, 35.2 ml (250 mmol) of trimethylamine are added dropwise over a period of 10 minutes. (45% in water), the temperature is set to 30 ° C. The pH value of solution is 7. Then the solution is heated to 40 ° C and 23, 15 g (250 mmol) of epichlorohydrin are added dropwise with stirring. The reaction temperature is maintained at 40 ° C and continue to mix the mass. After 6 hours at 40 ° C, cool the solution to 20 ° C and add 60 ml of isopropanol. The precipitated crystals are filtered, washed with acetone - menthol (4: 1) and dried in vacuum.
    The product (17.1 g), obtained with a yield of 30.2% (60.4% of theory), has So pl. 152-154 ° C. M -7, b (c - 1 in water).
    Example 9. Preparation of (-) - -3-chloro-2-hydroxy-propyl trimethylammonium 1-b - (+) - tartrate.
    150 g (1 mol) of L-tartaric acid
    weighed into 200 g of methanol. ,
    118.2 g (2.0 mol) of trimethylamine and 200 g of isopropanol are added at 20 ° C over 1 hour. The temperature is kept at. The tartaric acid dissolves to form di-trimethyl-ammonium-b - (+) - tartrate. Then, 185.0 g (2.0 mol) of epichlorohydrin is added and the temperature is held at 20 ° C. Withstanding this temperature, the mass is stirred for another 2 days, the precipitated crystals are filtered, washed with acetone - methanol (4: 1) and dried in vacuum.
    The product (170.5 g) obtained with a yield of 37.6% (75.2% of theory),
    4-24 p tv
    has m.pl. 154-155 C. (s - 1 in water).
    (oi);
    -9.7
    Example 10. Preparation of di- (-) - 3-chloro-oxy-propyltrimethyl-ammonium b- () -tartrate.
    150 g (1 mol) of L-tartaric acid are weighed into 200 g of methanol. At 20 ° C, 118.2 g (2.0 mol) of trimethylamine and 280 g of ethanol are added over 1 hour. The temperature is set to 35 C. The tartaric acid dissolves to form ditrimethylammonium -b - (- s) -tartrate. Then 185.0 g (2.0 mol) of epichlorohydrin is added and the temperature is maintained at 35 C. The temperature is 25 ° C. The mass is stirred for another 2 days. The precipitated crystals are filtered off, washed with acetone – methanol (4: 1) and dried in vacuo.
    The product (153.7 g), obtained with a yield of 33.9% (67.8% of theory), has so pl. 157-158 ° C. (o) -8.2 (s - 1 in water).
    Example 11. Preparation of di - - {(-) - 3-chloro-2-hydroxy-propyltrimethyl-ammonium —L - (+) - tartrate.
    150 g (1 mol) of L - (+) - tartaric acid are weighed 9 200 g of methanol. At 20 seconds, 118.2 g (2.0 mol) of trimethylamine and 280 g of ethanol are added over 1 hour. Set the temperature. The tartaric acid dissolves to form ditrimethyl ammonium b - (+) - tartrate. Then 185.0 g (2.0 mol) of epichlorohydrin is added and the temperature is kept at. Overheating this temperature, the mass is stirred for another 2 days. The precipitated crystals are filtered off, washed with acetone – methanol (4: 1) and dried in vacuo.
    The product (175.5 g), obtained with a code of 38.7% (77.4% of theory), has so pl. 155-15b with. (oi) p -9.5 (s - 1 in water).
    Example 12. Preparation of di (-3-chloro-2-hydroxy-propyltrimethylammonium -L - (+) - tartra and ta.
    To 18.75 g (125 mmol) of L - (+) - BHH-acid, dissolved in 10 ml of water and 60 ml of isopropanol, 13.3 g (225 nmol) are added dropwise with stirring for 10 minutes. trimethylamine and 18 ml; the temperature is kept at 30 ° C. The pH value of the solution is 7. Then the solution is cooled to 25 ° C and 20.8 g (225 mmol) of pichlorohydrin are added dropwise with stirring. Tempe0
    five
    0
    five
    Reagent the reaction, hold at and continue to mix the mass. After 6 hours at 25 ° C, the solution is cooled to 15 ° C and 60 ml of isopropanol are added. The precipitated crystals are filtered off, washed with acetone - methanol (4: 1) and dried in vacuum.
    The product (16.2 g), obtained with a yield of 28.6% (57.2% of theory), has so pl. 150-151 ° C. (o) -6.4 (s - 1 in water).
    Example 13. Preparation of d- - (-) - 3-chloro-2-hydroxy-propyltrimethyl-ammonium —L - (+) - tartrate.
    To 18.75 g (125 mmol) of L - (+) - tartaric acid, dissolved in 10 ml of water and 60 ml of isopropanol, 13.3 g (225 mmol) of trimethylamine are added dropwise over a period of 10 minutes. and 18 ml, the temperature being maintained at 30 ° C. The pH value of the solution is 7. Then the solution is cooled to 25 ° C and 23.8 g (275 mmol) of epichlorohydrin are added dropwise with stirring. The reaction temperature is held at 25 ° C and the mass is kept stirring. After 6 hours at 25 ° C, the solution is cooled to and 60 ml of isopropanol are added. The precipitated crystals are filtered off, washed with acetone - methanol (4: 1) and dried in vacuum.
    The product (160.5 g), obtained with a yield of 35.4% (70.8% of theory), has so pl. 152-153 ° C. (° C), -7.1 (s - 1 in water).
    Example 14. Preparation of di- - (-) - 3-chloro-2-hydroxy-propyl 4) and methyl ammonium-L - (+) - tartrate.
    150 g (1 mol) of L - () - tartaric acid are weighed into 200 g of methanol. At 20 ° C, 130.0 g (2.2 mol) of trimethylamine and 280 g of ethanol are added over 1 hour. The temperature is set to 20 ° C. The tartaric acid dissolves to form ditrimethyl ammonium b - (+) - tartrate. Then 203.6 (2.2 mol) of epichlorohydrin is added and the temperature is maintained at. Overheating this temperature, the mass is stirred for another 2 days. The precipitated crystals are filtered off, washed with acetone - methanol (4: 1) and dried in vacuum.
    The product (160.5 g) obtained with a yield of 35.4% (70.8% of tert.),
    I have a Tt.pl. 152-1514: (fti) -7.1 (s - 1 in water).
    Example 15. Obtaining (-) - -3-chloro-2-hydroxy-propyltrimethylammonium chloride.
    228.3 g (0.5 mmol) of di - (-) - 3- -chloro-2-hydroxy-propylmethylammonium -b- (+) - tartrate are dissolved in a mixture containing 315 ml and 135 ml of ethanol at room temperature . Within 2 minutes, 38.2 g (0.5 mol) of solid KCl was added to the mixed solution. KCl was dissolved within 2-3 minutes. To this solution was added 49.4 g of HCl (37% in ULO) 0.5 mol). When added, K, H-tartrate precipitates, and the pH value drops to 3.2.
    The reaction mixture is stirred for 1 h at room temperature, cooled to and sucked K, H-tartar under suction, washed with alcohol - water and dried in air.
    The yield is 94.2 g (100.1%), (oi) ° 31.5 ° (c - 1.1 M NaOH).
    The filtrate (and washing solvent) is evaporated on a rotary evaporator at a bath temperature of 50 ° C until (-) - 3-chloro-2-oxo-propyltrimethylammonium chloride is removed. The mixture is then cooled to room temperature. Crystals of (-) - 3-chloro-2- -oxy-propyltrimethylammonium chloride are filtered off with suction, washed with this NOL-acetone and dried. Yield 88.5 g (47.0%), (ot) |, -29, / (s - 1,),
    The mother liquor and industrial solvent are evaporated to dryness.
    The residue is digested with 160 ml of absolute ethanol at 70 ° C. The suspension is cooled in an ice bath. Crystals of (-) - 3-chloro-2-hydroxy-propyl trimethyl ammonium chloride are sucked off with suction, washed with ethanol - acetone and dried.
    Output 83.6 g (44.5%), (od) p -29.3 (s - 1).
    Example 16 Preparation of (-) - -3-Chloro-2-hydroxy-propyltrimethylammonium chloride,
    228.3 g (0.5 mol) di - (-) - 3-hlop -2-oxy-propyl-methyl-ammonia | -L- - (-) - tartrate at room temperature is dissolved in a mixture containing 315 MP and 135 ml of ethanol. Over a period of 8 minutes, 88.9 g of HCl (37%) is added dropwise to the mixed solution.
    five
    0
    five
    with
    0
    five
    0
    five
    0
    five
    in 1 LO, 0.9 mol), and then for 10 min the mixture containing 28.1 g of CPC (0.5 mol) in a 30 ml field, K, H-tlr-waste immediately drops out in the form of crystals. The reaction mixture is stirred for 1 h at room temperature, cooled to 4 ° C and sucked K, P-tartrate on suction, washed with ethanol - and the extract is in air.
    I Yield 94.6 g (100.8%) (Y) + 31.3 ° (s - 1.1 M NaOH). (-) - 3- -chloro-2-hydroxy-propyltrimethylammonium-chloride was isolated in Example 15.
    Example 17, Obtaining (-) - -3-chloro-2-hydroxy-propyltrimethylammonium-chloride,
    K, H-tartrate was prepared according to Example 15 of 228.3 g (0.5 mol) of di - (-) - -3-chloro-2-hydroxy-propyltrimethylammono- (+) - tartrate and filtered.
    Then the filtrate and the washing solvent are evaporated on a rotary evaporator to a weight of 350 g. Then 600 ml of toluene are added and the remainder of the water is azeotropically removed.
    After distillation, approximately (150) g of water precipitates (-) - 3-chloro--2-hydroxy-propyltrimethylammonium chloride as crystals. The heterogeneous mixture is cooled to room temperature and sucked off with suction, the crystals are washed twice with 25 mp of ethanol - acetone (1: 1) and dried.
    Yield 17.65 g (93.6%) (-) - 3-chloro-2-hydroxy-propyltrimethylammonium chloride, (oi) -29.8 (s - 1, O.N),
    Example 18, Obtaining (-) - -glycidyltrimethylammonium-chloride ((-) - S, S, K, -trimethyl-oxirane methane-amine),
    K 9.5 g (50 mmol) (-) - 3-chloro--2-hydroxy-propyltrimethylammonium chloride (99.1%), (oi) -29.5 ° (s -1, HjO), t, b1, 212-214 ° C), dissolved in 35 ml of methanol, a solution of 2.7 g of Na-methanolate (50 mmol) in 45 of methanol was added dropwise at room temperature with stirring. Then the mixture was stirred for 3 h, then the precipitated sodium chloride (2.7 g, 92.4%) was filtered and washed twice with 5 ml of methanol. Finally, the filtrate and the washing ethanol are evaporated. The crude product (8.75 g, 115%) is placed in 50 MP of chloroform, in which it gradually dissolves after shaking, and only 1K | chiach11-solid amount of insoluble .. NnCl remains. Undissolved NaCi (0.2) g, 8.5%) was filtered.
    After evaporation of the CHCl 2, 7.6 g (99.9%) of (-) - glycindyltrimethyl ammonium chloride are obtained.
    The product does not contain the source material (according to those), so pl. 121-125.5 ° C. (с) -27.0 (с - 1 in water).
    Example 19. Preparation of (-) - -glycidyltrimethylammonium chloride ((-) - N, N, S, -trimethyl-oxirane methane-amine).
    To 9.5 g (50 mmol) (-) - 3-chloro-2-hydroxy-propyltrimethylammonium-chloride (99.1%), U} -29.5 ° (s - 1, H, 0) m.p. 212-21A ° C), dissolved in 35 ml of methanol, a solution of 3.25 g of KOH (86%, 50 mmol) in 45 ml of methanol is added dropwise with stirring. Then the mixture was stirred for 3 h, then the precipitated KCl was filtered (3.55 g, 96%) and rinsed with 5 ml of ethanol twice. Finally the filtrate and industrial ethanol are evaporated. The crude product (8.28 g, 109%) is placed in 50 ml of chloroform, in which it gradually dissolves after shaking, with a small amount of undissolved KGL remaining. Insoluble KCl (0.20 g, 5%) is filtered off. After evaporation of CHCl.sub.7, 7.55 g (99.4%) of (-) - glycidyltrimethyl ammonium chloride are obtained.
    The product does not contain the starting material (according to TLC), so pl. 12 123.5 ° C. (-26.8 (s - 1 in water).
    Example 20. Obtaining (-) - -carnitinitrile.
    15.2 g (0.1 mol) (-) - glycidyltrimethylammonium chloride (99.4%, (oi) -27.0 ° (s - 1, HjO), mp 121-123 C) , dissolved in 16 ml of water and then cooled to 10 ° C. A 50% aqueous solution of hydrocyanic acid (HCN, O, 1 mol) is then added over a half hour and the mass is stirred for 3 hours at 20-25 ° C. The reaction mixture is evaporated on a rotary evaporator and recrystallized from methanol.
    15.5 g of L-carnitinitrile (86.8%) are obtained in the form of colorless crystals.
    from m.p. 253 ° s (with decomp.). (S) n: 9.4 ° (s - 1 in water).
    Example 21. Preparation of D-carmine nitrile.
    but). Production of di- (+) - 3-chloro-2-oxy-propyltrimethyl l-D - (-) - -tartrate.
    15.0 g (0.1 mol) of B - (-) - tartaric acid are weighed into 20 ml of methanol. At 20 ° C, 11.8 g (0.2 mol) of trimethylamine and 28 ml of ethanol are added over 1 hour. The temperature is maintained at 20 ° C. The tartaric acid is dissolved to form di-trimethyl-ammonium-D - (-) - tartrate. Then, 18.5 g (0.2 mol) of epichlorohydrin is added and the temperature is maintained at 20 ° C. With this temperature maintained, the mass is stirred for another 2 days. The precipitated crystals are filtered off, washed with acetone - methanol (4: 1) and dried in vacuum.
    The product (14.8 g), obtained with a yield of 32.3% (64.6% of theor.), Has so pl. 153-155 ° C. (ci) + 9.4 ° (s - 1 in water).
    b). Preparation of (+) - 3-chloro-2-hydroxy-propyl trimethylammonium chloride.
    To 18.35 g (40.5 mmol) of tartrate of Example 21a in 65 ml of water, 4.50 g (40.5 mmol) of calcium chloride dissolved in 15 ml of water was added dropwise to the vessel. Calcium tartrate immediately precipitates as crystals. After 5 minutes, the suspension is cooled in an ice bath (the solution has a pH value of 7), and the calcium tartrate is filtered under suction. After washing with methanol and drying in air, it weighs 10.40 g (theoretical weight of tetrahydrate is 10.54 g, yield 98.7%).
    The filtrate (and the methanol wash) is evaporated on a rotary evaporator at a bath temperature of 50 s. The solid residue weighs 16.4 g (1, 5, 24 g from theory). It is digested with 25 ml of absolute ethanol at 70 ° C. The slurry is cooled in an ice bath and the crystals are filtered on suction. After washing with ethanol-acetone (1: 1) and acetone, air drying is carried out.
    Output 10.5 g of colorless crystals (68.9% of theory), so pl. 211-212.5 ° C. (ei) -1-29, 1 (s - 1 in water).
    at). Preparation of (+) - glyzndyltrimethylammonium chloride (+) - N, N, N-trimethyloxnranmethanamyl).
    To 9.5 g (50 mmol) (+) - 3-chloro-2-oxy-propyl trimethlammonium chloride (99, U. Coij-p -29.1 ° (s - 1, so pl. 212-214 , 5 C), dissolved in 35 ml of methanol, with stirring at room temperature, a solution of 3.25 g of KOH (86%, 50 mmol) in 45 ml of methanol is added dropwise. The mixture is stirred for 3 hours, the precipitated KCl (3.6 g, 36.6%) are filtered off and washed twice with 5 ml of ethanol, and the filtrate and washing ethanol are then evaporated.
    The crude product (8.35 g, 110% is mixed with 50 ml of chloroform. By shaking, the product can be gradually dissolved except for an insignificant amount of KCl (0.15 g 4%), which is filtered off.
    By evaporation of the SISC, 7.6 g (99.9%) of (+) - glycidyl trimethylammonium chloride are obtained.
    The product according to TLC does not contain the source material. M.p. 122-123.5 C, (ci) J + 27.1 ° (s - 1 in water).
    d). Preparation of (+) - carnitine nitrile chloride.
    To 10 ml of methanol were added 4.35 g of acetone cyanohydrin (98%, 50 mmol) and 7.9 g (50 mmol) of (+) - glycidyltrimethylammonium chloride. The resulting mixture was stirred at 20-25 ° C until complete dissolution of the components. Then, the resulting solution was heated to 45 ° C for half an hour and continued to stir for 4 hours at the same temperature (checking the reaction progress based on TLC data), and after half an hour at 50 ° C the target product began to fall out. The resulting mixture is cooled to 20 ° C, after which the white crystals formed are sucked off on suction, rinsed three times with acetone (6 ml each) and finally dried.
    Output 7.35 g (82.3% of theory), so pl. 249 ° C (with decomp.). (oi) d +25.4 (s - 1 in water).
    The resulting product, based on data from BHH, turns out to be 97.9% and contains another 1.4% (+) - glycidyltrimethyl-ammonium chloride. As a result of recrystallization from ethanol (95%), long needles with m.p. 256 С
    five
    0
    five
    0
    about 5
    0
    five
    (with different). W) +25.9 (s - 1 in water).
    Example 22. Preparation of di - (+) - -3-chloro-2-hydroxy-propyltrimethylammonium) -B - (-) - tartrate.
    The method is carried out analogously to Example 8 with the exception that 0 - (-) - tartaric acid is used. The product (15.6 g), obtained with a yield of 22.5% (55.0% of theory), has so pl. 154-155 ° C. (Oi) J +9.5 (s - 1, W NaOH).
    The method is carried out analogously to example 11, with the exception that B - (-) - tartaric acid is used. The product (171.9 g), obtained with a yield of 37.9% (75.8% of theory), has so pl. 155-156 ° C. (s) + 9.5 ° (s - 1, H, 0).
    The method is carried out analogously to example 12, with the exception that D - (-) - tartaric acid is used.
    The product (14.0 g), obtained with a yield of 27.4% (54.8% of theory), has so pl. 151-151.5 ° C. (ci) + 7.2 ° (s - 1, HjO).
    b). Preparation of (+) -; 3-chloro-2-hydroxy-propyl trimethyl ammonium chloride.
    The method is carried out analogously to example 15, with the exception that tartrate is used according to examples 22a. K, N-tartrate (93.8 g) is obtained in 99.7% yield. (oi) ° -31.4 (, 1 M NaOH.
    The target product (86.9 g) is obtained with a yield of 46.2%, (oi) p + 29.6 ° (s - 1, H 0).
    The method is carried out analogously to example 16, with the exception that tartrate is used according to examples 22a. K, H-tartrate (94.4 g) is obtained in a yield of 100.6%, (ot) -30.8 ° (s-1,).
    The target product (87.2 g) is obtained with a yield of 46.4%, (Yur + 29.8 ° (s -1,).
    at). Preparation of (+) - glycidyltrimethylammonium chloride.
    The method is carried out analogously to example 4, except that the product according to examples 226 is used. The product (7.4 g), obtained in a yield of 96.7%, has mp. 123-123.5 ° C. (o6) p + 27.0 ° (s - 1, HjO).
    The method is carried out analogously to example 5, except that the product according to examples 226 is used. The product (7.6 g), obtained in a yield of 99.0%. has 120-120.5 C. (oL) +27.0 (s-1, H, 0).
    The method is carried out analogously to example 18 with the exception that the product according to examples 22b is used. The product (7.55 g) obtained in 98.5% yield has a mp. 122 ° C. (l;), 8 ° (s-1, HjO).
    d). Preparation of (+) - Carnitine Nitrile Chlord.
    The method is carried out analogously to example 20 with the exception that the product according to example 21c is used. 15.1 g of (+) - carnitine nitrile chloride (8A, 4%) are obtained in the form of colorless crystals with m.p. 254 С (with decomp.), (Ci) p +25,8 (s -1,)
    The proposed method is simpler and is carried out in fewer stages. In the known method, the initial B, and -carnitine nitrile-chloro-RID is converted in 2 stages using D-camphorsulfonic acid oxide to obtain the corresponding salts and transfer them to the corresponding diastereomers, separating the desired diastereomer and separating it.
    In addition, the known method involves the use of silver salts, therefore, in order to prevent
    no blackening of the reactants etch should
    lead in the dark.
    权利要求:
    Claims (1)
    [1]
    Invention Formula
    The method for producing optically active carnitine nitrile chloride using optically active tartaric acid, characterized in that, in order to simplify the process, optically active tartaric acid dissolved in water or suspended in C, -C-alcohols is reacted with trimethylamine followed by addition epichlorohydrin at 10-35 ° C to obtain optically active di- (3-chloro-2-hydroxy propyltrimethylammonium) tartrate, which is cleaved with hydrochloric acid in the presence of an alkali salt or alkaline earth metal salt and the salt of this metal tartaric acid and optically active 3-chloro-2-hydroxypropyl trimethylammonium chloride is converted into optically active glycidyl trimethyl ammonium chloride, which is reacted with acetone cyanohydrin or hydrocyanic acid, by a strong base in methanol.
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    同族专利:
    公开号 | 公开日
    EP0157315B1|1988-06-01|
    CS266568B2|1990-01-12|
    CA1238923A|1988-07-05|
    IL74553A|1990-06-10|
    TR22235A|1986-10-10|
    SU1329616A3|1987-08-07|
    US4732999A|1988-03-22|
    CH658857A5|1986-12-15|
    HU195764B|1988-07-28|
    PL252722A1|1985-12-03|
    JPS60231632A|1985-11-18|
    US4732709A|1988-03-22|
    DE3563044D1|1988-07-07|
    YU142287A|1988-04-30|
    EP0157315A3|1986-07-02|
    AU4019185A|1985-10-10|
    RO92320B|1987-10-02|
    PL148361B1|1989-10-31|
    BR8501627A|1985-12-03|
    IL74553D0|1985-06-30|
    AT34738T|1988-06-15|
    DD236922A5|1986-06-25|
    DK153185D0|1985-04-03|
    DD232036A5|1986-01-15|
    CS248785A2|1989-04-14|
    MX160765A|1990-05-09|
    NO162717C|1990-02-07|
    BG44373A3|1988-11-15|
    HUT39412A|1986-09-29|
    ES8603379A1|1985-12-16|
    FI850682A0|1985-02-19|
    YU53485A|1988-02-29|
    BG43863A3|1988-08-15|
    EP0157315A2|1985-10-09|
    ES541848A0|1985-12-16|
    AR240309A1|1990-03-30|
    IN164370B|1989-03-04|
    NO162717B|1989-10-30|
    NO851388L|1985-10-07|
    ZA851960B|1985-11-27|
    FI850682L|1985-10-05|
    AU570780B2|1988-03-24|
    US4670192A|1987-06-02|
    DK153185A|1985-10-05|
    RO92320A|1987-09-30|
    US4692543A|1987-09-08|
    CN85101426A|1986-09-24|
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    CN102329243B|2011-10-12|2013-11-20|浙江工业大学|Tubular reaction method of L--3-chloro-2-hydroxypropyl trimethyl ammonium chloride|
    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    CH1704/84A|CH658857A5|1984-04-04|1984-04-04|OPTICALLY ACTIVE DITARTRATE.|
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