• 专利附录
  • 专利说明
  • 权利要求
  • 类似技术
  • 同族专利
  • 引用文献
  • 法律状态
  • 优先权
    • 专利摘要:
    New 4-diphenylmethylene-1-hydroxybenzyl-piperidines having the formula wherein A1, A2, A3 and A4, taken separately, each represents hydrogen, halogen, trifluoromethyl, alkyl containing 1 to 4 carbon atoms or alkoxy containing 1 to 4 carbon atoms, and the pharmaceutically acceptable acid addition salts thereof possess valuable pharmacological properties. In particular, they are blood circulation activating and anticonvulsive.
    公开号:SU772482A3
    申请号:SU782562702
    申请日:1978-01-10
    公开日:1980-10-15
    发明作者:Живкович Душан
    申请人:Юцб С.А. (Фирма)；
    IPC主号:
    专利说明:

    The invention relates to a process for the preparation of new, not described in literature, 4-diphenylmethylene-1-hydroxyben zilpiperidines of the general formula: where R. - Cd is independently hydrogen or halogen, one halomethyl or alkyl or alkoxyl with 1-4 carbon atoms, or their salts which have pharmacological properties. in particular, they have a beneficial effect on the cerebral, peripheral and coronary circulation, as well as an anti-spasmodic effect on the central nervous system. The patent and technical literature is extensively describing the alkylation of piperidine with haloalkyls 1. The aim of the invention is to develop a process for the preparation of new piperidine derivatives or their salts with valuable properties. The goal is achieved by the proposed method, which is based on the known above reaction. According to the invention, a method for the preparation of 4-diphenylmethylene-1-hydroxybenzylpiperidines of the general formula I or their salts is described, which consists in that the 4-diphenylmethylenepiperidine of the general formula KI R4 has the indicated values. the derivative is subjected to benzyl condensation of the general formula X-Young where X is halogen, Rg. is a hydroxy-protecting group, such as benzoyl, in the presence of an acid acceptor in an inert solvent followed by alkaline hydrolysis of the compound thus obtained and liberating the desired product in free form or in the form of salt.
    Preferably, xylene is used as the inert solvent, and an inorganic base, such as sodium carbonate, is used as the acid acceptor.
    Pharmaceutically acceptable acids, for example hydrochloric acid, are used to isolate the desired product as a salt.
    Example. 1, 4- (4-tert-Butyldiphenylmethylene) -1- (4-hydroxybenzyl) -piperidine.
    and For 4 hours, a mixture of 18, .4 g of 4- (4-tert-butyldiphenylmethylene) -piperidine, 20 g of 4-benzoyloxybenzyl bromide and 9.5 g of anhydrous sodium carbonate in 50 ml of xylene is heated at 120 ° C. The reaction medium is filtered after cooling to separate the sodium bromide formed, and the filtrate is extracted with dilute hydrochloric acid (15 ml of concentrated hydrochloric acid, diluted in 40 ml of water). 1- (4-Benzoyloxybenzyl) -4-.C4-tert-butyldiphenylmethylene) -piperidine is precipitated in the form of its hydrochloride, which is slightly soluble and which is separated by filtration. It is recrystallized in isopropanol. Output 85%, mp. 259261 ° C (isopropanol).
    b) A mixture of 10 g of the previously obtained compound and 10 g of potassium hydroxide in 200 ml of ethanol is heated under reflux. Continue to distil the alcohol and gradually replace it with water. After distilling off the alcohol, dilute hydrochloric acid (20 ml of concentrated hydrochloric acid, diluted in 25 ml of water) is added slowly. The slightly soluble hydrochloride precipitates and is separated upon decantation of the reaction medium. The precipitate is then washed twice with warm water and recrystallized. In isopropanol to obtain 4- (4-tert-butylphenylmethylene) -1- (4-hydroxybenzyl) -piperidine hydrochloride, m.p. 202-204С (isopropanol). Yield 72%.
    The following intermediate (stage a) and target (stage b) compounds were prepared in a similar way.
    The melting points shown, unless otherwise indicated, are the melting points of the hydrochloride. In fact, the melting points are often not very clear (deviation limits of 1-5 ° C), this is because the compounds obtained often contain small amounts of solvent.
    2) 4- (4-tert-Butyldiphenylmethylene-1- (2-hydroxybenzyl) -piperidine
    a) S.zbN ,, -, 102HC, mp, 205-207 ° С (isopropanol)
    b) C qH g NO-HC, so pl. 150-152C (acetonitrile)
    3) 4-Diphenylmethylene-1- (4-hydroxybenzyl) -piperidine
    a) C2 29 02, t.pl. 246-248c (isopropanol)
    b) ,. NA, so pl. 244-24 bps (isopropanol), 189-190 С (free
    base)
    4) 4-Diphenylmethylene-1- (3-hydroxybenzyl) -piperidine
    a) SzzN Od. HC1, m.p. 249-251 seconds
    b) With dNgbO.NS, so pl. 148-150 C (acetonitrile)
    5 4-Diphenylmethylene-1- (2-hydroxybenzyl) -piperidine
    a) C32H2pN02.-HCl, m.p. 214-21b With
    b) Cgs Nd5.YOH.CF, so pl. 156-158C (acetonitrile) (softens already at
    132С), 148-149 С (free base)
    6) 4- (2-Chlordiphenylmethylene) -1- (4-hydroxybenzyl) -piperidine a) CsgHggCINOg-HCl, m.p. 26426S (isopropanol)
    6) C25-tt24CNO-HC1, so pl. 248250 C {isopropanol), 193-194C (free base) - so pl. fumarate 130-140 ° C, so pl. maleate 110-112s.
    7) 4- (2-Chlordiphenylmethylene) -1- (3-hydroxybenzyl) -piperidine
    a) C, m.p. 254256 0 (isopropanol)
    ) C, H.CING-HCI, so pl. 242244 0
    8) 4- (2-Chlordiphenylmethylene) -1- (2-hydroxybenzyl) -piperidine
    a) С, „Н - ,, С1МО„ - НС), so pl. 200202 ° C 26
    b) C25-H24CINONS, so pl.
    9) 4- (3-Chlordiphenylmethylene) -1- (4-hydroxybenzyl) -piperidine
    a) C aHggClNO - HC1, so pl. 242244 ° C (isopropanol)
    b) C25 H 24CINOHC1, m.p. 23423b ° C isopropanol
    10) 4- (3-Chlordiphenylmethylene) -1- (3-hydroxybenzyl) -piperidine
    a) С ,,, Н5йС1НО „НС1, so pl. 221223 ° С
    b) C25H24C1NO.H1, m.p. 156157 with isopropanol
    .11) 4- (4-Chlorophenylmethylene) -1- (4-hydroxybenzyl) -piperidine a) C „„ H “dC1NO-. HC1, m.p. 244246 0
    b) Cgj H Cl-NO-HCl, so pl. 232-233 C (isopropanol)
    12) 4- (4-Chlordiphenylmethylene) -1- (3-hydroxybenzyl) -piperidine
    a) C. "N" DC) HC1, so pl. 1921940s
    .6) With ,, H54C1NOHC1, so pl. 1431450s (benzene)
    13) 4- (4-chloro-phenylmethylene) -1- (2-hydroxybenzyl) -piperidine
    a) 1 NOg HC1 (per molecule of acetone crystallization), so pl. 112-114 ° C (acetone) b) C 5 24C 0-MS so pl. 240-241c 14) 4- (4-Fluorodiphenylmethylene) -1- (4-hydroxy-benzyl) -piperidine a) Cj2H2efNOg-HCl, m.p. 233234C (isopropanol) b) HC1, so pl. 230-232 (benzene) 15) 4- (4-Fluorodiphenylmethylene) -1- (3-hydroxybenzyl) -piperidine a) Cz2NoeRMO „-NS, so pl. 227, 228 ° C (benzene) b) Ci H FNOHCl, so pl. 125-126 (benzene) 16) 4- (4-Fluorodiphenylmethylene) -1- (2-hydroxybenzyl) -piperidine a) C.E2H28 OIIS1., So pl. 100102С (benzene) b) С2зН24 0 C1, so pl. 211-213 17) 4- (3-Fluorodiphenylmethylene) -1- (4-hydroxybenzyl) -piperidine a) CaoHoaFfJOo HC1, so pl. 254256 C (benzene) b) Cr H PMOHCI, so pl. 242-. 24b ° C (isopropanol) 18) 4- (3-Fluorodiphenylmethylene) -1- (3-hydroxybenzyl) -piperidine a) Cz2HsfiFNOg-HC1, so pl. 241243 ° С (xylene) b) C H24FNO-HC1, so pl. 145147 ° C (acetonitrile) 19) 4- (2-Fluorodiphenylmethylene) -1- (4-hydroxybenzyl) -piperidine a) C52H2 in OOHS1,. m.p. 267269 ° С (isopropanol) b) C25Ha4NO НС1, so pl. 245-247 20) 1- (4-hydroxybenzyl) -4- (4-trifluoromethyldiphenylmethylene) -piperidium a; Cjj., - HC1, so pl. 242 ri H V. b) C2 H24F3NO-HC1, so pl. 228229 ° C (ethyl acetate) 21) 1- (3-hydroxybenzyl) -4- (4-trif methyldiphenylmethylene) -piperidine a) Cz, H2e FjNOjjHC1, m.p. 201203 0 (Egyl acetate) b) C-ft H xF NO-HCl, m.p. 129131 C 22) 1- (4-hydroxybenzyl) -4- (3-trimethyldiphenylmethylene) -piperidine a) NO, -HC1, mp. 229231 C (methanol) b) CjjHa FjjNO-HCl, so pl. 229230C (ethyl acetate) 23) 1- (3-hydroxybenzyl) -4- (3-trif methyldiphenylmethylene) -piperidine a) e H ,, oFaNO, HC1, m.p. 215217 C b) C26H24F NO-HC1, T. PL. 148-1 24) 1- (2-hydroxybenzyl) -4- (3-tri-methyldiphenylmethylene) -piperidine a) The benzoyloxy derivative was hydrolyzed without isolating b) C26H.24FxNO- HC1, m.p. 158-15 ((isopropanol) 25) 1- (4-hydroxybenzyl) -4- (2-trif methyldiphenylmethylene) -piperidine a) C HjgFjNOj. HC1, m.p. 242244 0 b) .F., N0-HC 1, m.p. 2502S2C (methanol) 26) 1- (2-Oksibe.chzil) -4- (2-trifluoroethyldiphenylmethylene) -piperidine a) C, 0. HC1, m.p. 12527 C S C-H F-N0 .NS, so pl. 13234 ° C 21) 1 -. (4-Hydroxybenzyl) -4- (4-methoxy-, phenylmethylene) -piperidine). ,,., NO.J- HCl, m.p. 243b) C2.6H27 NOj. HC1, m.p. 222-223 0, 28) 1- (2-hydroxybenzyl) -4- (4-methoxy-diphenylmethylene) -piperidine a) No. g-HC1, so pl. 115-120 ° C ethyl acetate) (low definition) b) HsvNO-j.-NS), so pl. 2 3-224 ° С 29) 1- (4-hydroxybenzyl) -4- (2-methoxy diphenylmethylene) -piperidine a) NO, -HC1, mp. 242-243 ° С isopropanol) b) C26H27N02.-HC1, T.PL. 251-252 ° C 30) 1- (3-hydroxybenzyl) -4- (2-methoxy diphenylmethylene) -piperidine a) Ci-iH-i, HC1, t.cl. 210-212С (BonzolU b) C.2J, t.p. 220-222 ° C (isopropanol) 31) 1- (2-hydroxybenzyl) -4- (2-methoxyphenylmethylene) -piperidine a) C j H ,, 1 N0, - HC1, m.p. 181-182s b) Co N tMO-g. NA, so pl. 128-130s (benzene) 32) 4- (3,4-Dimethyldiphenylmethylene) 1- (4-hydroxybenzyl) -piperidine a), -NC, m.p. 2b7-2b8 ° C methanol b) C27H2 NO.HCI, so pl. 248-250 ° C 33) 4- (3,4-Dimethyldiphenylmethylene) 1- (3-hydroxy-Isyl) -piperidine a) Cj Hj NO --HC1, m.p. 235-23 bs (isopropanol) b) Cj-jH O-HC, so pl. 147-149 0 (benzene) 34) 4- (3,4-Dimethyldiphenylmethylene) 1- (2-hydroxybenzyl) -piperidine a) C H NOj-HC, so pl. 162-164 with b) C, H.j, NO-HC, so pl. 203-205С (ethyl acetate) 35) 4- (4-Chloro-4-fluorodiphenylmethien) -1- (4-hydroxybenzyl) -piperidine a) Cz2H, C HC, So pl. 221-. (benzene) b) (jHjjCl FNO-HC, (per 1 molecule of enzol crystallization), so pl. 1343bs 36) 4- (4-Chloro-4 fluoriphenylmethyl-, en) -1- (3-hydroxybenzyl) -piperidine. a) CjjH C FNO HC, So pl. 236238 With (e-propanol) b) L2st 2; } f Q- (i, mp. 229-230 0 37) 4- (4-Fluoro-4-trifluoromethyldipheylmethylene) -1- (4-hydroxybenzyl) -piperiine a) mp. 222-229 С (isopropanol ) b) C2, H2 / N0НС1, so pl. 223-225 with (benzene) 38) 4- (4-Fluoro-4-trifluoromethyldiphenylmethylene) (3-hydroxybenzyl) -piperiine
    a) The benzoyloxy derivative was hydrolyzed without isolation.
    b) C2 (,. HCl, mp. 134-135 ° C (acetonitril)
    39) 4- (4-Fluoro-3-trifluoromethyldiphenylmethylene) -1- (4-hydroxybenzyl) -piperidine
    a) CgaHjyF HC1, so pl. 21b-218c (benzl;
    b) N0-HC1, so pl. 234-235С
    40) 4- (4-Fluoro-3-trifluoromethyldiphenylmethylene) (3-hydroxybenzyl) -piperidine
    a) C, H2 / N0.2 HC1, so pl. 174-17b with (ethyl acetate)
     b) N0 HC1, m.p. 133-135 ° C. 41) 4- (4-Ftop-4-methoxydiphenylmethyl) -1- (4-hydroxybeisyl) -piperidine
    a) C H, so pl. 223-225С
     OZ p
    (ethyl acetate)
    m.p. 219-220 ° C
    b) C2j, H2 / N02 -HN (. Isopropanol.
    42) 4- (4-Fluoro-4-methoxydiphenylmethylene) -1- (3-hydroxybenzyl) -piperidine
    m.p. 195-197С
    a) (ethyl acetate) 140-141C
    b) HC1, m.p. (isopropanol)
    43) 1- (4-hydroxybenzyl) -4- (4-propoxydiphenylmethylene) -piperidine
    a) C jHgjNO, HC, mp, 204–20b ° С (acetonitril)
      HC1, m.p. 225-227 ° С
    6) (acetonitril 7
    44) 1- (4-hydroxybenzyl) -4- (4-isopropyl diphenylmethylene) -piperidine CoJk NO HCl, m.p. 253-254 ° С (et1 .2.0
    nol)
    45) 4- (4-Chloro-3-methyldiphenylmethylene) -1- (4-hydroxybenzyl) -piperidine
    . With ", H-, SemO-NS, so pl. 221-223 ° C
    Jjdo i: c7.
    (ethyl acetate)
    46) 4- (4,4-Dichlorodiphenylmethylene) -1- (4-hydroxybenzyl) -piperidine
    m.p. 166-168 С
    Cj H cejNo-Hci
    (isopropanol).
    权利要求:
    Claims (1)
    [1]
    Invention Formula
    Method for preparing 4-diphenylmethylene-1-hydroxybenzylpiperidines of the general formula
    wherein, independently of one another, one hydrogen or halogen, one halomethyl or alkyl or alkoxy with 1-4 carbon atoms, or their salts, characterized in that 4-diphenylmethylene piperidine of the general formula
    where they have the indicated values, .25 is condensed with a benzyl derivative of the general formula
    where is x
    halogen,
    5 a hydroxy-protecting group, such as benzoyl, in the presence of an acid acceptor in a ty-iepTHOM solvent, followed by alkaline hydrolysis of the compound thus obtained and separation of the target product in free form or in salt form.
    Sources of information taken into account in the examination 1. Heterocyclic compounds. Ed. R. Elderfield, M., ed. IL 1953, vol. 1, p. 515-517.
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    同族专利:
    公开号 | 公开日
    SE7800184L|1978-07-12|
    CS195652B2|1980-02-29|
    FR2376846A1|1978-08-04|
    NL7800146A|1978-07-13|
    FR2376846B1|1983-02-04|
    DK5778A|1978-07-12|
    SU990761A1|1983-01-23|
    FI780028A|1978-07-12|
    BE862769A|1978-07-10|
    PT67511B|1979-06-11|
    LU78839A1|1978-09-18|
    ZA78158B|1978-10-25|
    GB1542823A|1979-03-28|
    JPS5387367A|1978-08-01|
    ES465861A1|1978-09-16|
    IL53766D0|1978-04-30|
    NO780040L|1978-07-12|
    DD134089A5|1979-02-07|
    DE2800919A1|1978-07-13|
    JPS6125031B2|1986-06-13|
    CA1101426A|1981-05-19|
    IT7847573D0|1978-01-10|
    PL203912A1|1979-06-04|
    IT1103117B|1985-10-14|
    BG28574A3|1980-05-15|
    PT67511A|1978-02-01|
    引用文献:
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    US4650874A|1984-11-26|1987-03-17|G. D. Searle & Co.|N--4 piperidines|
    US4628095A|1985-06-05|1986-12-09|G. D. Searle & Co.|Substituted N-benzyl-4- piperidines|
    EP0228893A3|1985-12-20|1990-01-03|A.H. ROBINS COMPANY, INCORPORATED |Arylalkyl-heterocyclic amines, n-substituted by aryloxyalkyl group in allergy treatment|
    GB9000305D0|1990-01-06|1990-03-07|Pfizer Ltd|Anticholinergic agents|
    DE19681115D2|1995-12-20|1999-11-25|Eckhart Pein|New 1-phenylalkyl / alkylene-4 -piperidine derivatives and their use as serotonin antagonists|
    ES2237078T3|1998-01-16|2005-07-16|Eisai Co., Ltd.|PROCEDURE TO PRODUCE DERIVATIVES OF DONEPEZILO.|
    WO2004060371A1|2002-12-18|2004-07-22|Fmc Corporation|N--4- piperidines and pyridines|
    US7683077B2|2003-05-20|2010-03-23|Ajinomoto Co., Inc.|Piperidine derivative|
    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    GB931/77A|GB1542823A|1977-01-11|1977-01-11|Piperidine derivatives|
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