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    • 专利摘要:
    The method of obtaining the substituted 2- -amnnoalkoks. And 1,7,7-trimethyl-bicyclo
    公开号:SU1253425A3
    申请号:SU3219704
    申请日:1980-12-12
    公开日:1986-08-23
    发明作者:Будаи Золтан；Магданьи Ласло；Лаи Аранка；Мезеи Тибор；Грашшер Каталин；Петец Луиза；Кошоцки Иболиа
    申请人:Эдьт Дьедьсерведьесети Дьяр (Инопредприятие)；
    IPC主号:
    专利说明:

    The invention relates to a process for the preparation of new substituted 2-amino-alkoxy-1,7,7-trimethyl-bicyclo (2,2,1) -heptains of the general formula
    125
    one)
    de r
    l "C, -SlNgT O-A-kS R Vg
    - phenyl, chloropheny,
    -alkoxyphenyl, phenyl- (-Cj-alkyl) chlorophenyl- (-e-alkyl) or thienyl; the same or different C: -Cd-alkyl, C-C -gbl-alkyl or together form d-C, -a lkylene, oi, ") - C-C-oxaalkylene, uJ-C-Su-azaalkylene with benzyl group at the nitrogen atom
    A is C.-Cg. -H-or isoalkylene; It means a simple bond of ot or -configuration, or their conjunction, possesses analgesic, antiepiptical, and sensitization D1gstvie.
    The purpose of the invention is to obtain new compounds with isy spectrum of activity and low toxicity.
    Example 1. () -2-Benzyl-2- (3-dimethylaminopropoxy) -1,7,7- -trnmetsht-bicyclo (2.2, O heptane.
    To a suspension of g (0.1 mol) of sodium amide in 100 ml of anhydrous benzene is added a solution of 24, g (0.1 mol) of (1) -2-benzyl-1,7,7-trimethyl-bicyclo (2, 2.1) heptane-2-ol in 100 ml of anhydrous benzene with constant stirring at the boiling point. After the addition is complete, the reaction mixture is heated to boiling until the formation of ammonia is complete. With stirring, the reaction mixture was added to the reaction mixture with a pg of 13.4 g (0.11 mol) of 1-dinethylamino-3-chloropropane in 20k anhydrous benzene. The reaction mixture is heated to the boiling point for 6 hours, then cooled to, rinsed three times with Porka water. Bo 40 ml and extracted with a solution of 15 g (0.1 mol) of tartaric acid in 50 MP water or O, IM water brine solution; Aqueous acidic solution when cooled to a temperature of 0 - (- 5)
    3425, 1
    ammonia solution to pH 10. The oily base that was separated out was extracted with dichloroethane. After removal of the solvent, the resulting residue is subjected to fractional distillation under reduced pressure. Obtain 30.2 g (92%) of the desired product in a light yellow
    oils. T, 140-146 C / 26, 7Pa.
    Getting sour fumarate.
    16.5 g (0.05 mol) of the above base are dissolved in 20 ml of acetone and 5.8 g (0.05 mol) of fumaric acid and 60 ml of hot water are added to the solution. After cooling, the precipitated crystals are filtered and dried. Yield: 20.5 g (92%), T / 103-104 C.
    K (
    N
    -) 6.4.
    five
    0
    five
    0
    five
    octanol
    water Found,%: C 69.04; H 9.02; K 3.09.
    CjfiHj, N05 (435,606)
    Calculated,%: C, 70.08; H 8.82 j 3.14,
    Getting hydrochloride.
    3.3 g (0.01 mol) of the above base is dissolved in 25 ml of anhydrous ethyl acetate and the solution is acidified with a saturated solution of hydrogen chloride in an ethyl acetate at a pH value of 5. The crystals that enter are filtered and dried. Yield 3.5 g (95%). T „, 146-148 ° C.
    Found,%: C 72.01, H 9.78} Ct 9, B 7,
    N 3.80.
    CjjH gCtNO (365.99).
    Calculated,%: C, 72.19; H, 9.90; Ct, 9.69; N 3.83.
    Getting citrate.
    6j6 g (0.02 mol) of the above base is dissolved in 10 ml of acetone; To the resulting solution is added a solution of 3.8 g (0.02 mol) of citric acid in 300 ml of ethanol. The superior salt is filtered and dried. Yield 9.59 g (89%). .
    Found,%: C 62.13; H S, 37; N2,68.
    0
    0.5N .., 68)
    Calculated,%: C, 62.31, and 8.40; N 2.60,
    Getting tartrate ..
    A solution of 3.0 g (0.02 mol) of 55 tartaric acid in 30 ml of ethanol is added to a solution of 6.6 g (0.02 mol) of a naped base in 10 mp of acetone. The precipitated tartrate is filtered and dried. Yield 8.82 g (92Z).
    PA
    92 94 S.
    Found,%: C 65.37; K 8.71, N2.87
    C, 1, t (79, b2)
    Calculated,%: C 65, P, And 8.62, N 2.92.
    Getting iodomethyl.
    To a solution of 6.6 g (0.02 mol) of the said base in 50 ml of acetone is added a solution of 2.82 g {0.02 mol of methyl iodide in 50 ml of acetone. The reaction mixture was allowed to stand overnight at room temperature in the dark. The precipitated product is filtered and dried. Yield 8.3 g (88%). T, 187-189 ° C (with decomp.).
    rtA
    35
    Found,%: C 58.68; P 8.24; J27.05; N 2.93.
     (471.48)
    Calculated,%: C 58.59; H 8.12; J 26.92; N 2.97.
    Example 2. (+) - 2-Benzyl-2- - (3-dimesh1-amino-2-methylpropoxy) -1.1,7-trimethyl-bicyclo (2.2.1) heptane
    To a suspension of 2.4 g (0.1 mol) of sodium hydride in 100 ml of anhydrous toluene is added dropwise at 90 ° C with stirring a solution of 24.4 g (0.1 mol) of () -2-benzyl-1.7 , 7-trimethyl-bycyklo (2,2,1) -heptan-2-ol in 100 ml of anhydrous toluene. The reaction mixture is heated at t30 C h, then a solution of 16.5 g (0.11 mol) of 1-dimethylamino-3-chloro-2-methylpropane in 20 ml of anhydrous toluene is added, the mixture is heated at 8 h, then cooled, boiled with a solution of 16.5 g (O, 1I mol) of tartaric acid and 80 ml baud. The aqueous phase is alkalinized with concentrated aqueous ammonia at a pH of 10 and extracted with dichloroethane. The dichloroethane phase is dried over anhydrous magnesium sulphate and evaporated. The obtained non-reference base without purification is converted into acid fumaratch. Yield 31 g (90%). Sour fumarate melts at HO-IAS C.
    Found,%: C 71.02; H 8.90 jN3.01. 50
     (459,633)
    Calculated,%: C, 70.55; H 8.99; N 3.04.
    Example 3. (±) -2-Benzylg2- - (2-dibelpropylaminostoxy) 1,7,7- -trnmethyl-bicyclo (2.2.1) heptane.
    The process is conducted by analogy with example 1 with the difference that in
    five
    40
    3.9 g (0.1 mol) of sodium amide, 24.4 g1 (0.1 mol) (5:) - 2-benyl-1 7, 7-trimethyl-bi1-clo (( 2,2,1) heptane-2-ol and 18.0 g (0.11 mol) of 1-diisopropyl-amino-2-chloroethane. Get the target product in the form of a light yellow oil in the amount of 30 g (80,7%). T 190-191 C / 133 Pa. Sour fumarate melts octanol water
    at 128-130 ° C. K (-) 1.15.
    15
    25
    0
    five
    0
    20
    Found,%; C, 71.9; H, 9.33; N2.89 j CjgH.NOg (487.687)% j C 71.42; H 9.3; N 2.87.
    Example 4. (t) -2-BeH3iw-2;. - (4-benzylpiperazinyl) -propoxy -1, 7,7-trimethyl-bicyclo (2.2.1) heptane. The process is carried out by analogy with example 2 with the difference that 3.9 g (O, t mol) of anide lgate, 24.4 g (O, t mol) of () -2-benzyl - -1,7,7-trimethyl-bicyclo (2,2,1) heptane--2-ol and 27,8 g (Oh, And mol) 1-beisyl-4- (3-chloropropyl) -piperazine . The desired product is obtained in the form of a yellow viscous oil in the amount of 38 g (82.6 Z). Double-acid fumarate pgavits at 207–209.5 ° C.
    Found,%: C 67.25, H 7.68; K44.04. , (692,861). Calculated,%: C 67.5; H 7.57, N 4.03.
    EXAMPLE 5. (1) -2-Benzyl-2- - (3 -diisopropylaminopropoxy) -1,7,7- -trimet L gbicyclo (2.2.1) heptane.
    The process is carried out by analogy with example 2 with the difference that 2.4 g (0.1 mol) of sodium hydride, 24.4 g (0.01 mol) of (f) -2-benzyl are used as starting materials. -t, 7,7-trimethyl-bicyclo (2,2,1) heptane-2-ol and 19,65 g (O, 11 mol) t-diisopropyl - 5 amino-3-chloropropane, yield target. product 36.05 g (93.5%). The acid fumarate melts at 93-95 C.
    Found,%: C, 71.50; H 9.61; m 2.69, C5 (, H4TN05 (501.714) Calculated,%: C 71.82; H 9.44, N2.79.
    PRI mme p1 6. (±) -2-Benznl-2- - (3-diethylaminopropoxy) -1,7,7-. -trimetsh1-bicyclo (2.2, Ogeptan.
    The process is carried out by analogy with example 2 with the difference that g (0.1 mol) of sodium hydride is used as starting materials.
    0
    51251425tf
    2l4, ff (0.1 mol) () -2-benzyl-1,7,7-2A, D g (0.10 mol) () -2-Renzyl-1, -trimethyl-6-cyclo- (2.2 , 1) heptane-2- 7,7-trimethyl-bicyclic (2,2,1) heptane-2- -ol and 16, A6 g. (O, 11 mol) 1-diethyl-amino-3-chloropropane. Target output
    -ola and 18.0 g (0.11 mol) of 1-chloro-3-morpholineopropane. Target output
    product 33 g (92.4%). Sour fumarate product j 30.37 g (82.3%). Sour
    melts at 123.5-125, З C.
    Found,%: C 71.40; And 9.06; N2.98,
    fumarate melts at 76-78 C.
     (473.66)
    Calculated,% S C 71.00; H 9.15; N 2.96. "O
    Example 7. P - (-) - 2-Benesh1- - (3-dimethyl finopropoxy) -1,7,7- -trimethyl-bi-hydroxy (2,2,1) heptane,
    The process is carried out by analogy with example 1 with the difference that 3.9 g (0.1 mol) of sodium apad, 24.4 g (0.1 mol) B - (+) - 2 -benzyl-1,7,7-trimethyl-6-cyclo (2.2.1) heptane-2-ol. +13.72 (, etaiol) and 13.4 g of 20 (0.11 mol) of 1-dimethylamino-3-chloro-. sir The target product is obtained in the form of a light yellow oil in the amount of 30.87 g (93.7Z). ISO-ISe C /. / 133.3 Pa. (ot) °. -2,175 (eta 25 iol). The sour 4 fumarate melts at
    4fi t / .0r- v I octanol h with CG
    . 144-145 S. K (- ---) 5.57.
    {Bypass
    (d.). j, -1.66 (, ethanol).
    Found,% g C 70.48; H 8., 89, -N 3,10. ZO
    CieHjgNOg (445,608)
    Calculated,%: C, 70.08; H 8.82, N 3.14.
    Example 8. P - (+) - 2-BeMsyl-2- - (2-diethylaminoethoxy) -I, 7,7-trimethyl-bicyclo (2.2.1) heptane.
    The process is carried out by analogy with example 1 with the difference that 3.9 g (0.1 mol) of sodium amide, 24.4 g (0.1 mol) 1) - (+) - 2 are used as starting compounds. -beNsyl- t J 7,7-trimetsh1-bitsshlo- (2,2,1) heptane-2-ona and 14,9 g (0.11 mol) of 1-diethylamino-2-chloro) ethane. The expected product 9 is obtained as a light yellow oil in the amount of 29.9 g (87%). TKU 57-bZ ° C / 53.3 Pa. (N). 48 °
    rs "nD
    (, ethanol).
    Found,%: C 70.74; H 9.12; N3.09
    35
    40
    Found,% 5 C 68.26; H 8.40; N2.84,
    CjgHjj NO (487.62)
    Calculated,%: C 68.96 {H 8.48, N 2.87.
    I'll try it on. (1) -2- (GL "- methylaminopropoxy) -2- (4-methoxy-phenyl) -1,7,7-grimethyl-bicyclo (2.2" t) heptane.
    The process is carried out by analogy with example 2 with the difference that 3.9 g (0.1 mol) of sodium amide, 26.0 g (0.1 mol) (+) - 2 (4 - methoxyfennl) -bicyclo (2.2.1) heptane-2-ol and 13.4 g (0.11 mol) of 1-dimethylaminr-3-chloropropia. The yield of the target product
    26.8g (77.5%). The acid fumarate melts at 148-149 C.
    E is found,%: C 67.6; H 8.48jW 3.00 28 “3 OB L06)
    Calculated,%: C, 67.65; H, 8.52; N, 3.03.
    Example 11. (±) -2- (n-Chlorobenzyl) -2- (3-dimethylaminopropoxy) -1.7,7-trimethyl-6-cyclo (2.2, O-heptane ..
    The process is carried out by analogy with example 1 with the difference that as starting compounds, 3.9 g (0.1 mol) of sodium amide are used as starting compounds,
    27.9g (0.1 mol) (t) -2- (h-xnop6eH-zil) -1,7,7-trimethyl-bicyclo (2.2.1) heptane-2-yl and 13.4 g (0 , 1 mol) of 1-dimethylamino-3-chloropropane. The target product is obtained in the form of an esque oil in an amount of 32.5 g (89.3%).
     kip 71-173 C / 46.7 Pa. Sour Fuma
    45
     (459,633)
    Calculated,%: C, 70.55; H 8.99, N 3.05 ..
    GG im im 9 (1) -2-Benzyl-2- - (E-morpholinopropox) -1,7,7-trn-methyl-bicyclo- (2,2,1) heptane.
    The process is carried out by analogy with example 2 with the difference that the starting materials used are
    50
    rat melts at 145-46 C, K (
    octa ol water
     3.64.
    Found,%: C 64.90 H 8.6A; 017.2 N 2.83 ..
    C HjjClNOs (480.06)
    Calculated,%; C 65.0.5; And 7.98; CE 7.39; N 2.91.
    Example 12 (±) -2-101-Chlorben zsh1) -2- (2-dimethylaminoethoxy) -1,7,7 55 -Grymetsh1-bicyclo (2.2.1) heptane.
    Pro, ess is carried out by analogy with example 1 with the difference that, as starting compounds,
    product 30.37 g (82.3%). Sour
    fumarate melts at 76-78 C.

    Found,% 5 C 68.26; H 8.40; N2.84,
    CjgHjj NO (487.62)
    Calculated,%: C 68.96 {H 8.48, N 2.87.
    I'll try it on. (1) -2- (GL "- methylaminopropoxy) -2- (4-methoxy-phenyl) -1,7,7-grimethyl-bicyclo (2.2" t) heptane.
    The process is carried out by analogy with example 2 with the difference that 3.9 g (0.1 mol) of sodium amide, 26.0 g (0.1 mol) (+) - 2 (4 - methoxyfennl) -bicyclo (2.2.1) heptane-2-ol and 13.4 g (0.11 mol) of 1-dimethylaminr-3-chloropropia. The yield of the target product
    26.8g (77.5%). The acid fumarate melts at 148-149 C.
    E is found,%: C 67.6; H 8.48jW 3.00 28 “3 OB L06)
    Calculated,%: C, 67.65; H, 8.52; N, 3.03.
    Example 11. (±) -2- (n-Chlorobenzyl) -2- (3-dimethylaminopropoxy) -1.7,7-trimethyl-6-cyclo (2.2, O-heptane ..
    The process is carried out by analogy with example 1 with the difference that as starting compounds, 3.9 g (0.1 mol) of sodium amide are used as starting compounds,
    27.9g (0.1 mol) (t) -2- (h-xnop6eH-zil) -1,7,7-trimethyl-bicyclo (2.2.1) heptane-2-yl and 13.4 g (0 , 1 mol) of 1-dimethylamino-3-chloropropane. The target product is obtained in the form of an esque oil in an amount of 32.5 g (89.3%).
     kip 71-173 C / 46.7 Pa. Sour Fuma
    rat melts at 145-46 C, K (
    octa ol water
    )
     3.64.
    Found,%: C 64.90 H 8.6A; 017.24, N 2.83 ..
    C HjjClNOs (480.06)
    Calculated,%; C 65.0.5; And 7.98; CE 7.39; N 2.91.
    Example 12 (±) -2-101-Chlorobenz1) -2- (2-dimethylaminoethoxy) -1,7,7- -Grimetsh1-bicyclo (2.2.1) heptane.
    Pro, ess is carried out by analogy with example 1 with the difference that, as starting compounds,
    3.9 g (0.1 mol) of sodium amide, 27.9 (O, 1 mol) () -2- (l-Chlorbeneyl) -1.7 7-trimethyl-bicyclo (2.2, I) heptane; 2- -ola and 1A, 9 g (0.11 mol) of 1-diethyl-amino-2-chloroethane. The desired compound is obtained as a viscous oil in the amount of 35.4 g (93.7%). T „162
    t67 C / 26.7 Pa. Plaviooctanol acid fumarate
    )
    with at 110-P2 S. to (
    water
     5.64.
    Found,%: C 65.12, H 8.31, Ct 7.08; N 2.77. Cj H ClNOj (494.08)
    Calculated,%: C 65.54, H 8.16; CS 7.7; N 2.83.
    Example 13. (-) - 2- (3 -Di-i-methylamino-2-methyl) -propoxy 1 2- (h-chlorphenyl) -1,7,7-trimethyl-bicyclo (2.2.1) heptane.
    The process is carried out by analogy with example 1 with the difference that 3.9 g (0.1 mol) of sodium amide, 26.5 g (0.1 mol) (+) - 2- (h -chlorophenyl) -1,7,7-trimethyl-bicyclo (2.2.1) heptane-2-ol and 16.5 (0.1 mol) 1-dimethylamino-2-methnl-3-chloropropane the compound is obtained as a light yellow oil in an amount
    32.3g (88.7%). T. „154-158 С / / 26.7 Pa. Sour fumarate melts
    at 159.5-162 ,, to ()
    water
     2.7.
    Found,%: C 65.30; H 8.15, C 17.38; N 3.03-CjgHjgClNOg (480.06)
    Calculated,%: C 65.03, H 7.98; C8 7.381 T 2.91.
    Example 14. (1) -2- (3 -Di-methylaminopropoxy) -2-fenst-1.7,7-β-trnmethyl-6-cyclo (2.2.1) heptane.
    The process is carried out by analogy with example 1 with the difference that 3.6 g (0.1 mol) am (sodium salt, 23.04 (0.1 mol) (±) -2-phenyl -1,7,7-trimethyl-bicyclo (2.2.1) heptane-2-ol and
    13.4g (0.11 mol) of 1-dimethylamino-3-chloropropane. The target compound is obtained in the form of a light yellow oil in the amount of 28.6 (90.64%).
     157-160 ° C / 160 Pa. The acid fumarate melts at 169.5-171.5 seconds.
    Found,%: C 39.65; H 8.38; NZ, 18,
     (431.58)
    Calculated,%: C 69.58; H 8.64j N 3.24.

    34258
    Example 15. () -2- (2 -Dimethylaminoethoxy) -2-phenyl-1,7,7-trimethyl-bicyclo (2.2.1) heptane.
    3.9 g (0.1 g atom) of potassium are weighed into 100 ml of anhydrous xylene. Suspension in a nitrogen atmosphere with vigorous stirring while reacting with 23.04 g (0.1 mol) (±) -2-phenyl-1,7,7-trime-10 tyl-bicyclo (2.2.1) heptane-2-ol until the evolution of hydrogen is complete. While stirring, a solution of 10.3 g (0.11 mol) of 1-dimethyl-1-to-2-chloroethane in 30 ml of anhydrous solution is added.
    15
    20
    25
    thirty
    35
    0
    five
    0
    five
    xylene and the reaction mixture is stirred for 6 h at tOO C, then washed three times, in 50 ml portions, and extracted with a solution of 15 g (0.1 mol) of tartaric acid in 1 ml of water (or 0.11 M aqueous solution of salt acid). The aqueous acidic phase is basified with a 20% aqueous solution of potassium hydroxide when cooled to 0-5 ° C, the oily base is extracted with ether and the solvent is removed. The residue is subjected to fractional distillation under reduced pressure or converted to salt without purification. The expected product is obtained in the form of a light yellow oil in the amount of 25.2 g (83.6%). kip 131-135 C / 26.7 Pa. The acid fumarate melts at l80-t82 C.
    Found,% s C 69.05; H 3.44. Cj HjsNOs (417.55) Incorporated,%: C 69.03; H 8.45 N 3.35 ..
    Example 16. () -2- (3 -Diethylaminopropoxy) -2-phenyl-1,7,7-trimethyl-bicyclo (2.2, Oheptan.
    The process is carried out by analogy with example 1 with the difference that 3.9 g (O, 1 mol) of sodium amide, 23.04 g (0.1 mol) (1) 2-phenyl- 1.7,7-trimethyl-bicyclo (2.2.1) heptane-2-α-ol and 16.46 g (0.11 mol) of 1-diethy-amino-3-chloropropane. The yield of the target product is 23.5 g (68.4%). The acid fumarate melts at 160-163 °.
    Found,%: C, 70.58; H, 8.95; N, 3.05. - C ,, H, NOg (459.63) Calculated,%: C, 70.55; H 8.99; N 3.05 ..
    PRI me R 17. (t) -2- (2 -Diethylamino-toxy) -2- (2-thienyl) -1,7,7- -trimethyl-bicyclo (2.2, oheptan.
    The process is carried out by analogy with example 2 with the difference that in
    3.9 g (O, 10 mol) of sodium amide, 23.6 g (0.10 mol) of (1) -2- (2-thienyl - -1,7,7-trimethyl-bicyclo ( 2.2, t) heptane-2-ol and 14.9 g (0.11 mol) of 1-diethyl-amino-2-propane. The target product has 27.4 g (81.7 Z). Acidic fzgmarate Pleivits at 132,5-135 ,.
    K 2Sh “22 -.) M, 19. water
    Found,%: C 64.10; H 8.27; H 3.15; S 7.05.
    .HOgS (451.61)%: C 63.83; And 8.25;
    N 3.10, S 7.10.
    Example 18. (t) -2- (3 -Di-methyllaminopropox) -2 - (- 2 -thienyl) - -1,7,7-trimethyl-bicyclo (2.2.1) heptav
    The process is carried out according to: analogous to example 2 with the difference that 3.9 g (0.1 mol) amund sodium, 23.6 g (0.1 mol) (±) -2- (2 -thienyl) -1.7,7-trnmethyl-bicyclo- (2.2.1) heptane and 13.4 g (O, 11 mo) of 1-dimethyl amino-3-chloropropane. The yield of the target product is 30.7 (95.6%). Sour fumarate with l47-t49 C. K (
    octano11 water
    1.12.
    Found,%: C 63.45; R 9.20; NC, 7.36.
    With jHjjNQ S (437.61)
    Calculated,%: C 63.13; B 8.06;
    N 3.20; S 7.32.
    PRI me R 19. (1 -2-O-Diethylaminopropy) -2- (2 -nenyl) - -1,7,7-trimethyl-bicyclo (2,2,1) heptane
    The process is carried out by analogy with example 2 with the difference that 3.9 g (0.1 mol) a1 "1 da sodium, 23.6 g (0.1 mol) (((2-thienyl ) - -1,7,7-trimet1S-bits1splo (2,2,1) heptane--2-ol and 16,46 g (0.11 mol) of 1-diethyl amino-3-chloropropaia. The yield of the target product 32, 4 g (96.62). The fumarate melts at 113-ft5 C.
    Found C, 64.25; And 8.64; H 3.04; S 6.80.
    CjsHjjNOsS (465.6)
    Calculated: C 64.48; B 8.44; N 3.01; S 6.88.
    Example 20. (±) -2-Dimethyl-amyietrxy-2-nn -1,7,7-trimetnl-bicyclic (2.2.1) heptane.
    In a flask filled with nitrogen and equipped with a stirrer, put ml
    0
    five
    0
    five
    0
    anhydrous ether and 3.3 g finely chopped lty. 1-2 ml of 31.3 g (0.2 mol) of bromobenzene is added to the mixture during cooling. An additional amount of bromobenzene is diluted with 60 ml of anhydrous ether and added at this rate to the reaction mixture so that it remains at a constant boiling point of the scientific research institute. After the addition is complete, the reaction mixture is heated to boiling for another 1 h, cooled to room temperature, and excess lithium is filtered off. The half solution is injected into the reaction with a solution of 27.4 g (0.18 mol) of (t) -1,7,7- trimeti-bNcyclo (2.2.1) heptane-2-one in 50 ml of anhydrous ether at boil for 2 hours, after which a solution of 18.54 g (0.198 mol) of 1-di-methylamino-2-chloroethane in 20 ml of anhydrous ether is added. The reaction mixture is heated to reflux with a condenser for several hours until the end of the reaction. The reaction mixture is cooled to room temperature and washed with water until neutral. A solution of 20.88 g (0.18 mol) of fumaric acid in water (200 ml) is added. The precipitated crystals are filtered and dried. 68.9 g (91.7%) of (±) -2-dimethylamino-ethoxy-2-fench1-1,7,7-trimethyl-bicyclic-6 (2.2.1) heptane acid fumarate are obtained. T „, 180-182 C.
    Found,%: 668.93 ;, And 8.40; KZ, 27.
    .. (417.55)
    Calculated, 2; C, 59.03; H 8.45; N 3.35.
    Note 21. (±) -2-Benzyl-2- -f3 - (K-cyclohexyl-K-methium) -amino-propoxy -1,7,7-trimethyl-bicyclo (2.2.1) heptane.
    The process is carried out analogously with an example. 2 with the difference that 2; 4 g (0.1 mol) of sodium hydride, 24.4 g (0.1 mol) of (1) -2-benzyl-1.7,7 - - Trimetsh1-bicyclo (2,2,1) heptane-2- -o a and 41.5 g (0.11 mol) of 1- (H-cyclohexyl-N-methyl) -aminog 3-shschopropane as a solvent 140 ml anhydrous toluene and 60 ml of anhydrous dimethylformamide. The yield of the target product is 37.56 g (94.7t). The acid fumarate melts at (with decomp.).
    Found: C, 72.50; H 9.31; N 2.70.
     (513,73)
    111253 25. 12
    Calculated,%: C, 72.48, and 9.22. N2.73.
    D R and measure 22. (1) -2- (i-methoxy- -phenyl) -2- (3 -dkmetnlaminopropoxy) -. -1.7, 7-trimethyl-bi 11 Cyclo (2.2, 1) heptane.
    a) A Grignard reagent is obtained from 4.8 g (0.2 g atom) of magnesium shavings and 37.4 g (0.2 mol) of A-bromoanisole in 60 MP anhydrous ether and reacted with a solution of 30 g (0, 2 mol) (i -) - l 5 7,7-trimethyl-bicyclo (2.2.1) heptane-2-one in 20 ml of anhydrous ether. The reaction mixture is stirred for several hours and the Grignard complex is decomposed with a solution of 26 g of ammonium chloride and 80 ml.
    ice water. The ethereal solution is separated (431.579), dried over anhydrous sulfa; Calculated,%; C 69.57 H 8.64j
    Found,%: C 70.51; H 8.9, N
     (459.63).
    Calculated,%: C, 70.56; H 8.99 N 3.05.
    Example 24. () -2-Benzyl - (-2-dimethylaminostoxy) -1,7, 7-methyl bicycles 1. (2, 2,1) heptane.
    The process is carried out as described in measure T, with the difference that 36.64 g (0.15 mol) (+) - 2-benzyl 7-trimethyl-bicyclo (2.2.1) heptane is used as the starting materials. -ola and 17.22 g (0.16 mol) of 2-dim aminoethyl chloride. The yield of the target 15 product 43,54 g (92%).
    Found,%: C 69.62; H 8.52, N
    to
    tolume and evaporated under reduced pressure. The residue is purified by fractional distillation. 43.9 g (±) -2- (h-methoxyphenyl) -1,7,7-trimethyl-bicyclo (2.2J1) heptan-2-ol are obtained. The yield is 84.4%. The boiling point of the obtained viscous colorless small with a characteristic odor is 155-165 C / 73 Pa.
    b) The process is carried out by analogy with example 1 with the difference that a 50% suspension of 7.8 g (0.1 mol of sodium amide in benzene, 26.03 g (O, 1 mol ) () -2- (i-methoxyphenyl) -1.1,7, 7-trimeting | -bicyclo (2.2, 1) heptane -2-ol and 13.4 g (O, It mol) 1-di- methylamino-3-chloropropac. The target product is obtained in the form of a light yellow viscous oil in the amount of 29.7 g (85.96%). T acid fumarate 149-151 C.
    Found, Z; C, 8.01; H 8.6r, N 3.11
     (461.6)
    Calculated,%: C 67.76, H 8.52; N 3.03.
    45
    thirty
    Example 23. (n) -2-Benzyl-2- - (2 - methyl-3-dimethylaminopropoxy) -, .- 1,7,7-trimethyl-bicenclo (2, 2,1) heptane
    The process is carried out as described in Example 1, so that θJ | ichiemj that 3.9 g (0.1 mol) of sodium amide and 24.4 g (0.1 mol) of (+) - 2-benzyl are used as starting materials. -1,7,7- - trimethyl-bicyclo (2,2,1) heptane-2-ol and 15,03 g (0.11 mol) of 1-chloro-3-di-methylamino-2-methyl propane. The yield of the 55% product is 31.1 g (90.5%), the melting point of the acidic acid is 155-157 ° e; (o () + 5.63 (, fiOH).
    Found,%: C 70.51; H 8.9, N 3.01- ..
     (459.63).
    Calculated,%: C, 70.56; H 8.99; N 3.05.
    Example 24. () -2-Benzyl-2- - (-2-dimethylaminostoxy) -1,7, 7-trimethyl-bicycl1. (2, 2,1) heptane.
    The process is carried out as described in Example T, with the difference that 36.64 g (0.15 mol) (+) - 2-benzyl-1.7, 7-trimethyl-bicyclo (2.2 , 1) heptan-2 -ol and 17.22 g (0.16 mol) of 2-dimethyl-aminoethyl chloride. The yield of the target product is 43.54 g (92%).
    Found,%: C 69.62; H 8.52, N 3.30.
    five
    N 3.24.
    20 Example 25. (-f) -2-Benzyl-2- - (2-hexamethylenamino-toxo) -7.7-trimethyl-bicyclo- (2.2.1) heptane.
    25
    about
    five
    0
    five
    0
    The process is carried out as onHCfino in example 1, with the difference that 5.85 g (1.5 mol) of sodium amide, 36.6 g (0.15 mol) of (+) - 2-benzyl 1,7,7-trimethyl-bicyclic (2,2,1) heptane-2-ol and 28,46 g (0,176 mol) of 2-hexamethylene-imipoethyl chlorine. The yield of the target product 48 g (86.7%). Sour fumarate has a T = 164-167 C, (/) 2.47 (in 1; Et it). . .
    Found,%: C 71.7, H 9.0, N 2.9.
     ()
    Calculated,%: C 71.72; H 8.92; N 2.88.
    The analgesic, antiepileptic and sedative effects of the proposed compounds are studied as follows.
    The analgesic effect of the compounds to be tested is studied by the method of Wirth et al. White masts are administered 0.4 ml of 0.5% acetic acid and the characteristic pain reaction {$ 10 is fixed after 5 minutes. The test compound is administered orally I h before the introduction of acetic acid. EgM efficiency is indicated as a percentage inhibition, based on the control group. B tab. 1 shows the corresponding results as well as the toxicity values.
    Acute toxicity is determined by Neither male and female white mice (CFLP strains, weight 18-24 g). The test substance is administered orally at a dose of 20 ml / kg.
    13
    After the treatment, the animals are observed for 4 days. Toxicity (LDjjMr / kg) is determined graphically by the Litchfield-Wilcoxon method.
    The therapeutic index is calculated according to the following equation:
    Therapeutic index
    5firA t / 4 -
    bo
    Antineptic effect is determined on white eggs, as is studied) The 4th compound is administered orally. Inhibition of maximum electroshock is determined by the Swingard method. White vgaam (weight 20–25 g) using granular electrodes are shown and the state of paralysis by the action of electric current. Larameters; 50 Hz, 45 mA, 0.4 s. As a criterion for the anticonvulsant action, complete inhibition of the tonic fold is recognized as spasms of the lower limbs. Test substances are injected 1 hour before an electric shock. Sedation inhibition of penile tremoris was determined by the modified Banzinger method in white mice. The results are shown in Table. 2
    The effect on the orienting act (the effect of inhibiting motility), determined from white mice in an eight-channel J) evB apparatus according to
    25342514
    according to the Borsi method, the number of light gaps caused by the movements of animals is recorded (each group consists of 3 animals; a 30-minute oral treatment is used; an observation time of 30 minutes).
    Potentiation of hexobarbital anesthesia is studied as follows.
    10 Test conducted by the Kaergaard method. Each group of animals consists of 3 mice. The control group receives a 0.92% solution of sodium chloride at a dose of 20 ml / mg oral
    15 and after that - hexobarbital intravenously at a dose of 40 mg / kg. Animals with a positive reaction are counted in the treated group based on a 2.5-fold average sleep duration of the control group. The results are presented in table 3.
    Thus, as follows from the data table. 1-3, the compounds according to the invention have a high anti-epileptic activity and, as was first found for compounds of the 7,7-dimethyl-bicyclo (2.2.1) heptane series, have an analgesic and sedative effect, superior. efficacy known compounds exhibiting similar activity.
    Table 1
    1C) favor table. I
    Tav itza 2

    100
    78
    25
    80
    270
    to
    2 "40 25 461
    Editor E. Papp
    Compiled by Yu. 2 (roprv Tehred V.
    Order 4635/60 Circulation 379
    . VNIIPI Gosudomtvenvoro kos shteta SZhSR
    for inventions And oTtcftiimift 113035, Moscow Zh-35, Rvushsha "a6 ,, d 4/5
    . Production and printing company, Uzhgorod, ul. Project, 4
    278
    5000
    417
    4.4
    Proofreader I. Muska Subscription
    权利要求:
    Claims (1)
    [1]
    The method of obtaining substituted 2-ammoniaalkoxy-1,7,7-trimethyl-bicyclo (2.2.1) heptanes of the general formula
    H 3 C sn 3
    СНзР-0-Α-Χ R В .
    where R is phenyl, chlorophenyl, C, -C e -alkoxyphenyl, phenyl- (C < - ”-Cj-alkyl), chlorophenyl- (C; -C 3 -alkyl) or thienyl;
    . R ^ hRj - identical or different C, -C / -alkyl, C 3 -C 6 -cycloalkyl or together will please
    d. , h) -C 4 -C r -alkylene, s, uJ -C 4 -C 7 -oxaalkyl or o (, u) -C 4 ~ C -azalkylene with a benzyl group at the nitrogen atom /
    A is Cj-Cj-h- or isoalkylene;
    means a simple bond or a p-configuration, or their salt different in that 1,7,7-trimethyl-bicyclo (2,2, 1) heptanol-2 · of the general formula
    NCS SPZ
    CH3 / H R OH where R has the indicated meaning, is reacted with an alkali metal, its amide or hydride in an inert organic solvent, and then the resulting intermediate alcoholate is reacted with a substituted aminoalkyl chloride of the general formula
    C1-AN where R 5 , R ^ H A have the indicated meanings in an inert organic solvent when heated, followed by isolation of the target product in free form or in the form of a salt.
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    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    BE581863A|1959-08-06|
    GB895050A|1960-01-29|1962-04-26|Boehringer & Soehne Gmbh|New basic ethers|
    DE1108684B|1960-01-29|1961-06-15|Boehringer & Soehne Gmbh|Process for the production of new basic ethers|
    FR4468M|1963-08-18|1900-01-01|
    GB1085969A|1965-08-11|1967-10-04|Glidden Co|Insectiphobic compositions comprising terpene derivatives|
    US4118499A|1975-10-15|1978-10-03|Glaxo Laboratories Limited|Anti-anxiety and anti-parkinsonian 1-aminoalkyl-2-endo-chloro-7,7-dimethylnorbornanes|
    JPS6034925B2|1979-07-31|1985-08-12|Teijin Ltd|US5242934A|1992-03-02|1993-09-07|R. J. Reynolds Tobacco Company|Method for treatment of neurodegenerative diseases|
    US5212188A|1992-03-02|1993-05-18|R. J. Reynolds Tabacco Company|Method for treatment of neurodegenerative diseases|
    US5242935A|1992-03-06|1993-09-07|R. J. Reynolds Tobacco Company|Method for treatment of neurodegenerative diseases|
    US5227385A|1992-03-13|1993-07-13|Wake Forest University|Method for treatment of neurodegenerative diseases|
    US5288872A|1992-03-13|1994-02-22|Wake Forest University|Compounds for treatment of neurodegenerative diseases|
    US5187169A|1992-04-10|1993-02-16|R. J. Reynolds Tobacco Company|Method for treatment of neurodegenerative diseases|
    US5214060A|1992-04-10|1993-05-25|R. J. Reynolds Tobacco Company|Method for treatment of neurodegenerative diseases|
    US5276043A|1992-04-10|1994-01-04|R. J. Reynolds Tobacco Company|Method for treatment of neurodegenerative diseases|
    US5232932A|1992-05-21|1993-08-03|R. J. Reynolds Tobacco Company|Method for treatment of neurodegenerative diseases|
    US5242916A|1992-07-07|1993-09-07|R. J. Reynolds Tobacco Company|Method for treatment of neurodegenerative diseases|
    US5248690A|1992-07-07|1993-09-28|R. J. Reynolds Tobacco Company|Method for treatment of neurodegenerative diseases|
    JPH0626170A|1992-07-09|1994-02-01|Yodogawa Steel Works Ltd|Mounting construction of wallboard|
    JPH06193226A|1992-12-26|1994-07-12|Yodogawa Steel Works Ltd|Installation structure for wall plate member|
    US5652270A|1994-07-01|1997-07-29|Egis Gyogyszergyar Rt|Pharmaceutical compositions containing bicycloheptane ether amines and a process for the preparation thereof|
    HU214588B|1994-07-01|1998-04-28|EGIS Gyógyszergyár Rt.|Process for producing pharmaceutical compositions comprising bicycloheptane derivative having cck system inhibitory effect|
    KR100381558B1|1994-07-01|2003-08-19|에지스 지오기스제르기아르 알티.|Pharmaceutical composition and preparation method thereof|
    US5583140A|1995-05-17|1996-12-10|Bencherif; Merouane|Pharmaceutical compositions for the treatment of central nervous system disorders|
    HU226061B1|1996-10-17|2008-04-28|Egis Gyogyszergyar Nyilvanosan|1,7,7-trimethyl-bicyclo[2.2.1]heptane derivative, pharmaceutical compositions containing the same and process for their preparation|
    HU9900445A2|1999-02-24|2001-06-28|EGIS Gyógyszergyár Rt.|Process for producing --n,n--2-phenyl-1,7,7-trimethyl-bicyclo[2,2,1]heptane and intermediate of the same|
    HU227114B1|1999-05-11|2010-07-28|Egis Gyogyszergyar Nyilvanosan|--2-[n,n-]-2-phenyl-1,7,7-trimethyl-bicyclo[2.2.1]heptane of high purity and pharmaceutically acceptable acid addition salts thereof, process for preparation of them and medicaments containing the same|
    US6335372B1|2000-11-28|2002-01-01|Orion Corporation|Treatment of obsessive compulsive disorder|
    FI20002612A0|2000-11-28|2000-11-28|Orion Yhtymae Oyj|Combination therapy for the treatment of disorders in serotonin turnover|
    HU0103017A3|2001-07-18|2004-05-28|Egis Gyogyszergyar Nyilvanosan|Pharmaceutical composition for the treatment of diseases caused by impairment of cognitive functions and its use|
    GB0306604D0|2003-03-21|2003-04-30|Curidium Ltd|Second medical use|
    WO2004084905A2|2003-03-24|2004-10-07|University Of Florida|Use of 5-ht2c receptor activity affecting compounds for treating idiopathic hyperhidrosis and associated conditions|
    HU0301537A3|2003-06-03|2005-07-28|Egis Gyogyszergyar Nyilvanosan|Deramcyclane fumarate tablets and process for producing them|
    KR101493508B1|2013-02-18|2015-02-16|오스템임플란트 주식회사|Tooth bleaching composition|
    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    HU79EE2715A|HU179164B|1979-12-14|1979-12-14|Process for producing cycloalkyl-ethers of alkanolamines|
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