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    • 专利摘要:
    The method of obtaining phenylalkylamine derivatives of the general formula R2 .. RS A-CH-K 3 where R is an amino group, alkylamino (or a dialkylamino group with 1-3 carbon atoms in the apical R particles, a halogen atom; R, a chlorine atom or a dano group, 4 hydrogen atom, methyl; hydrogen atom, methyl | methylene or hydroxymethylene group, group of total R, - - hydrogen or chlorine atom, hydroxyl or methoxy | R - hydrogen atom or methoxy, E - I-propylene, unsubstituted or substituted by one or : two methyl groups, or their salts, characterized in that the compound is it has the formulas where R, R ,, R ,, Rj and B have the indicated meanings, X is a group of the general formula, it is Ek R, II —CO — CH—, —CHn, CH, –sn — R where R has the indicated meaning, is subjected to complex with a metal hydride or pyridineboron followed by isolation of the target product in free form or in the form of a salt.
    公开号:SU1172449A3
    申请号:SU813358171
    申请日:1981-11-27
    公开日:1985-08-07
    发明作者:Кек Иоганнес；Пипер Гельмут；Крюгер Герд；Ноль Клаус；Дэммген Юрген；Дидерен Вилли；Кадатц Рудольф
    申请人:Др.Карл Томэ Гмбх (Фирма)；
    IPC主号:
    专利说明:

    , -, 4ij) pie n i HIK and Il to 1; n (mm (111. VbHit}; iKMibix iipn; ii: iiij; H) ix (|) 1M {il: p () and alkamine, lol. -lach lUiuiiiMu iljap-ing macho1 | 1Hich1. ;; and 111: 1lmmi,; partly; ia HJ HDCiH to the clannya; 1; l ul1m; ii nrg) AND AND (Few;}) 1; ilal1 ilamin about (ijiopMyjibiitem Ts. 1 -.4XJ and CHF;) rm -t l-C1b H JJ ij X ../ K r; u K, - .hminogr viiiia, a, nkilami оlly or sprays, namino1l1up; am (; mo1) uls: ode 1–3, where i is the Alrylpion part of K, is a dalogen atom; i 5 - al ohm of chlorine or cia ;; o a) UN11a; R4 atom of Hoacipivia, r-etil: 20 R, - is an atom of n (J motil L is methylepop i.a and oximee, L1 nopa rpyiuia; B is group o: 1kp. (1). P 25., P // ,) By - ato.1 Iolor (la or chlorine; gilroxa or jtoxy /, 50: 7 - iioaopojia or mstoksi I -; n-irolich: - ;, achamesh ;; and: li or) am1-1ts (.lp1 , 1 go one day with methyl yichi gruniami IX CLXIICH ,, 1; oladak1id; x biologist-oh -..., koi, 1 cci ni Ti.io, and -Gast D1:; laisfia K1L1n noo l, ah ; .. HaiiccTHo isno.gp.ktnanis and quality. N.). Ist11 uyuscheg. on crowns a, ;; iij.iaii, cpOiuTii.t hydrohdo; 1Д1да 1 - (4-amch ;; ji,;, -dibrom- (1) C1i.ch) -2 - (- benzidamia i -JTa nola, (and noluchak with: that aii; l1. ami111x1h) on (1) P R, Hal / -. jfpyc-c-is 2 .C-Hal where R, is E5 Dorb or hydroxyl: R, Ib is each hydrogen, alk il, - C 4 , “R., Kdodopo, NIZII1; adkil; ,, nizl ;; - 1 alK1; NO, HIJP DruG5 S, comilexpium hydrosome meth: ial and nGai-where is the solvent at a temperature of D from room temperature to the temperature of the dilution of solution ll. fi.M However, the instructions for the connection of the United Nations gives a week (Formatively high active assets, ate ;, and-i) n; e HH1IJA noJiVMtinu nonychsha; 1, feilkilkilov, o ;.padan1 yjiy4i; iiiiiibiM l.syngtni1 , m on KoniiHiioo ifiiHt. osta and ae nn a: aL, a.ni: -c i aega that so1la (a ::; teas, atijivaiMiHH LC) i I ::,; L C L a G i: a i-ai /; uly (1) - - -L / v. -: A-CIi NC .. In R i V - 5 K, - amine; l5i11 la, alkyls aon ;, lialkichaminlgo part1 i with the number of atoms (1H carbon dioxide 1 - 3;,. aluminum parts, Ri atom gallcha: a. I aH (m chlorine or cyazhlazulpa,} {- ;; G (l-1} Kv: cipo ;; a, babies ;:, with Ho; iop (v: a, revenge ;, l - metnnsnona and. ai scsim, .T1-; leHtJH; iH gyppa, B grugnta; M iine; i (b (; rmul; / 7-74 - 6 - Е f R d - atom of iodorol or chloe, O hydroxy :; and :: and methox ;, G hydrogen atom or. 1 ln 1) oiilsn, -leaaMCute nchiyi or 3aN t: i; icHHbiH (l; noi dum MSP: l yllmi roll: ami, cojieii, s;) edil (D1IS o (;; ei form with 9 Y- -C IiR X - J -, - - x / 1 1 I -ii X - r-pyii:; a common Oormul R ,, OH Rl, | j -CO-CH,, -ru-l IR has the indicated Z1 The start of the procedure is “reducing the reduction of the metal with metal hydride or L1ridineborade sdet - H1 to isolate 1; I eat the product in the c ;; obodm) as in the case of CCUHI. 3.1 The reaction is preferably carried out at room temperature to the boiling point of the reaction mixture. total (I) containing one, two or three optically active carbon atoms can be divided on its optically active antipodes, diastereomeric racemates, as well as optical antipodes by conventional methods, for example, fractional crystallization or chromatography. Example 1. 1- (4-Amino-3, 5-dichlorophenyl) (3-4-methoxy-phenyl-propyl -methylam1; 1-ethanol. To a solution of 3.45 g (9 mmol) 4 -amino-3, 5-dichloro-2-m- (3-4-methoxy-phenyl-propyl) -methylamino-acetophof non in 40 ml methanol and 15 ml of water are added in portions of 0.5 g (13.5 mmol of sodium borane). The pH value of the medium is maintained between 3 and 6 using 2N hydrochloric acid. After the addition of sodium borane is completed, the mixture is further stirred for 30 minutes and the solution is concentrated. The residue obtained is partitioned between 100 ml of ether and 100 ml of 2N ammonia. The ether phase is washed with water, dried over sodium sulfate and concentrated. The remaining oil is chromatographed on silica gel using a mixture of methylene chloride and methanol (19: 1) as eluent. The fractions containing the desired product are combined, evaporated and the solvent is removed from the resulting oil at 40 ° C. Yield 30%. IR spectrum (methyl chloride), cm: OH 3610, I 23400 + 3490; Cl2 2850 + 2940 OCHs 2830. Example 2. Hydrochloride of 1-4-amino-3, 5-dichlorophenyl-2- (N-phenylpropyl-methylamino) ethanol. 10 g (0.035 mol) of 4-a poly-2-bromo-3 -, 5-dichloro-acetophenone, 6.7 g (0.036 mol) of N-3-phenyl-propyl-methyl hydrochloride mn and 10.5 ml (0.075 mol) triethylamine is added to 250 ml of methylene chloride. This mixture is heated under reflux for 6 hours and then left to stand overnight at room temperature, washed with water, dried over cv: -; bd) aTCi i sodium and concentrated in a vzdzum. Oily residue, cond. Diy from crude 4-aMJiHO-3,5-dichloro-2- (N-3-cbenyl-popyl-methyl tino) -ac 94 tofenone, dissolved in 100 ml of 90% ethanol. While stirring and cooling with water, 5 g sodium borane is added in portions. The reaction mixture was allowed to stand for 1 hour at room temperature and the excess sodium borane was destroyed with acetone. After dilution with water, extracted with methylene chloride. The methyl chloride phase is separated, washed with water, dried over sodium sulfate and concentrated in a vacuum. The yellowish oily residue is chromatographed on silica gel using a mixture of methylene chloride and acetic acid ester (4: 1) as eluent. The fractions containing the desired product are evaporated. The remaining oily residue is dissolved in isopropanol, acidified with ethereal hydrochloric acid, and mixed with ether until crystallization begins. A colorless crystalline product is obtained. Yield 28%. T.il. starting with (during sintering). Example 3. 1-4-Amino-3,5-dichlorophenyl-2-N- (3-4-hydroxy-phenyl-1-methyl-propyl) methyl amino) ethanol. To an ice-cooled solution of 0.1 mol of 4-amino-3,5-dichlorop-2-N- (3-4-oxy-phenyl-1-methyl-propyl) -methylamino-acetophonone in 300 ml of tetrahydrofuran and 50 ml of water are added 0.2 moles of sodium borane while stirring. The reaction solution is further stirred for 60 minutes at room temperature with a TBNmepaType and after acidification with 2N. tetrahydrofuran is distilled off with hydrochloric acid. To the resulting water} ioMy hydrochloric acid residue is added 8.5 n. before the main reaction and then extracted twice with 250 ml of ether. The ether extracts are washed twice with 75 ml of water and dried with magnesium sulfate. The filtrate is concentrated and the residue obtained is purified on silica gel using a mixture of methylene chloride and methanol in a ratio of 30: 1 as eluent. The residue obtained after fractionation and condensation of the residue crystallizes after seeding. The crude crystallisate is recrystallized from methylene chloride and produces a mixture of diastereomeric racemates (1: 1). Yield 34%. M.p. 112-115 ° C. Example 4. 1-4-Amino-3-cyano-5-fluoro-phenyl-2-N- (3-4-methoxy-fecyl-propyl) -methylaminoJ-ethanol.
    amine and sodium borohydride. Yield 22% m.p. hydrochloride 17 C.
    NMR spectrum of base (): proton signal at carbon atom 1 of propanol part, doublet at 4.6 ppm. 5 Hz).
    Example 13. 1-4-mino-3-cyano-5-fluoro-phenyl-2-1- (3-4-methoxy-phenyl-propyl) -2-propylamino-ethanol.
    Example 2 is repeated, with the difference that 4-amino-3-cyan-3-fluoro-2-bromo-acetophenone, 1-4-methoxy-phenyl-3-2-propylamino-propane hydrochloride and sodium borohydride are used. Butter. Yield 26%.
    IR spectrum (methylene chloride) J cm: OH 3600, NH 3395 + 3495; OCH 2830; N-alkyl 28od; CrM 2220.
    Example 14. 1-4-Amino-3, 5-dichloro-phenyl-2-Hn- (3-2-methoxy-phenyl-propyl) -methylamino-ethanol hydrochloride,
    Example 2 is repeated, with the difference that 4-amino-3, 5-dichloro-2-bromo-acetophenone, 1-2-methokei-phenyl-3-methylstylamino-propane hydrochloride, triethylamine and sodium borohydride are used. M.p. 75 С (during sintering).
    Example 15. 1-4-Amino-3, 5-di-chloro-phenyl-2-H- (3-3,4-dimethoxy-phenyl-propyl) -methylamino-J-ethanol.
    Example 2 is repeated with the difference that 4-alumina-3, 5-dichloro-2-bromo-acetophenone, 1-3 hydrochloride, 4-dimethoxy-phenyl-3-methylamino-propane, triethyl-1H and sodium borohydride Oil, yield 20%.
    IR spectrum (methylene chloride), cm: OH 3600; NH.2 3390 + 3485; OCH 2830, N-alkyl 2800.
    Example 16. 1-4-Amino-3, 5-dichloro-phenyl-2-N- (3-4-phenyl-propyl) hydrochloride j
    -ethano-methoxy-with
    la
    Example 1 is repeated with a difference that 4 -a fflío-3, 5-dichloro-2- | H- (3-4-methoxy-feiyl-propsh) -amino-acetophenone and borg; 1, read, sodium in 90% ethanol. Oil, consumption of 16%. T.SH1. hydrochloride 185-186 0 (ethanol / ether).
    Example 17. Hydrochloride 1-4-A Shno-3, 5 - dichloro-feiyl-2- (H-3-phenyl-ppon; J -2-g Jor il-a IIHo) -ethanol.
    iiori op..ot iipiiMOp 2 with the difference:; to her that they use 4 -amino-3, 5-dichloro-2-bromo-at; etofenon, 1-phenyl-3-propylamino-propane hydrochloride, triethylamine and borohydride on three . Yield 15%. M.p. 124-128 ° C.
    Example 18. 1-4-Amino-3,5-dichloro-phenyl-2- N- (3-4-hydroxy-phenyl-1-methyl-propyl) amino-ethanol.
    Example 3 is repeated, with the difference that 4-amino-3, 5-dichloro-2-K- (3-4-hydroxy-phenyl-1-methyl-propyl) -amino-acetophenone and sodium borohydride in aqueous tetrahydrofuran. Dichloromethane, methanol and 19: 1: 0.5 concentrated ammonia are used as eluent for chromatographic purification on silica gel. Oil, 1: 1 mixture of diastereomeric racemates. Yield 35%.
    IR spectrum (KBg), cm: OH 23003500, (broadly aided.) NH 3460 + 3370; CH2 2920 + 2960, 1580; 1510 + 1480.
    UV spectrum (ethanol) A c, (, if, nm: 244 (0.28), 280 (0.08), 300 (0.08).
    UV spectrum (ethanol + KOH), nm 243 (0.54), 299 (0.15).
    Example 19.1-4-Amino-3,5-dichloro-phenyl-2-K- (3-4-methoxy-phenyl- -1-methyi-propyl) -amino | ethanol
    Example 3 is repeated with the difference that 4-amino-3, 5-dichloro-2-N- (3-4-methoxy-phenyl-1-methyl-propyl) al-1-acetophenone and sodium borohydride are used in aqueous tetrahydrofuran. Oil, yield 32%. The compound is a 1: 1 mixture of diastereomeric racemates.
    Yak-spectrum (methylene chloride), cm: OH 3600, NHg 3480 + 3390; CH 2930; COS 2830i fragrance. 1580 + 1485.
    UV spectrum (ethanol) Mate, nm: 2i4 (0.28), 280 (0.08), 300 (0.09). .Prm. 20. N- (2-4-AMiiHO-3, 5-dichloro-phenyl-eth-1) -Y- (3-4-hydroxy-fennl-1-methyl-propyl) -amin.
    Example 1 is repeated, with the difference that 4-amino-3,5-di-xjTop N- (3-4-hydroxy-phenyl-1-methyl-propyl) -phenyl-acetic acid amide and lithium aluminum hydride in tetrahydrofuran are used, and the reaction is wire t at the boiling point of the reaction mixture. Chromatographic purification is carried out by chromatography on silica gel (grain size 0.015-0.025 mm) under medium pressure using a mixture of methylene chloride, methanol and concentrated ammonia 19: 1: 0.1 as eluent. ; ml, HiiiXivi fiR /, l: r lUKlp (Mfrn, i (iix.:iop;ij,), cr,: Oil Ni) + TiHb; SI, G2 (; pkhtmat. OS 1t8 (; I 5 10-ti. К: l with UV- (Л1рктр (-ггакол). Макс, / (С, Л, il.iiiUil i.,: Н (;): jDi. (O.PN). viI) -: - rii44- ;-p (-ij and KV (-i-Ki i) mach. im: f (;, j3). UKi (П „| 6). 10 p and m t p 21, K- (2-: 1- Am1P (1-,) - likh.lor f1CH1il - 1ttsl) -; h (i-Lm (TO KS - (}) (L1il- 1 - methyl propyl), 12) jiTopHSOi lpi (p 1 with the 1st difference. lslg; 1l ezuyut, A-amio-3. 3-ji, i t5 chloro-M- (2-4-М1-1-; l hy phenyl- 1 -mo); LP1L,) - feilukg yCioii sour; i; a.siomogplril. lithi) alidro (}) ranrlem p (l ktsi10 spent at a temp) 1ЛГП1ЛП1Я р (л1кцио ии) and it (L, Kaëlo. P1: 1chol 62%. IR- ((.g eckhlooOO Cm. Ni.T 3- (80 + 3285; ClU 2930; AXIS 28 apobiaT. С, С 1580j 1310+ л185.;: - е gkktr (ethanol) f,, -., them: 25 242 (o, 23, pl eho). 280 (0.07), 302 (iijUH). Pgl-l e p 22. N- (2- | -Lmip; 1-3.:) - dicl (L1-1 e 1IL-1Ti: 1) -N- (, 3-3 ,, 4 - dime; -ok (; i-Flly: -lropi ;:) -meals};, zs Po; Tori from at .1er; with: that 1) ac1l1pey5 that u (l) amyl. 4-a-ino-3. 3-D1: xjujiJ-Nf 3, 4 dim1; gokei-1b (L11i: -lr (L1IL) -K-me1Il-6epl.pux: ye 1; oh ; sll: 0) s l ajjK; mogltstig; Lritsm Rlakdi:; lr. Water tsl gsg-gleratura kiltl yl-kll-opl1l. Oil, output L, IR infrared:; ecr (methyl it h.lotilL, e-.; N11 2 3493 + 3495; (ChlTs 2830, X - lkil 2800D. (L ek: -p (etaP: l |) 3 ,,,; .- ,, lm: l; and meer. 3.) Idr (l; loril. Ci - {--A-amipo-3, b-dlchloro-}) epil e1L1L,) - N- 1 3-g .; -2-methoxn-feiyl-11propyl) -methyl: - Ipa, Example 1 is repeated on the same 3 line that amyl is used by 4-ami AND; -3, 3-lilxjTop-N C 3 2-mstox; 1- | 1) (. L1i: LL roiyl) -stilphenylacetic acid and alumino-JQ lithium hydride, and the reaction is carried out at the time of n-boiling of rea.cdioppo;) PRI me R 24. K- (2-4-; l-1no-3, 5-dich.lor-fe1.yl-ethyl) -N-3-phenyl-, -propyl-methylamine. Example 1 is repeated, with the difference that the amide is 4-am-i1o-3, niX.; I (ip-K -; - flKHi;: -; iiii 4: ii.: IN-MC-T; l; lliiiiiiuiy xus; Hofi KHcj: oi4 ;; li a; i; MiUii; i) silt ligni, moreover,: lronolite L1L1 hh-miratourse Ki-kmll iu-ai iiiiitH:. M cjici,} ibi, -. I ;; /. IlK-CnLKllJ (PL -l: -:,: 1) 1: l. G-: Nil, G390 + 3 9P; ;,; - ;; :,. ::, / -: l At 1-C11Oct 1 (lLLALL :) in.,; . 2L5 (0,1: 0, (:;,. II pn., Er 1 :; Gal.;) Llchil l (2-4-a MI ii (j-3, 5 -Ju; xjK ; p - ;;) y 1; yl-HG l -N 3-4-methox1 -fgpyl-prolyl; -rsMHiia, Repeat (/ p 1 f ra; iii, lto 1 (L1O, L1lzuk aNiiij;; ; any-, -lix .nrip-N- (3-4 - r- i g;); al1-; pN1; l - l 1NL1L i) - (;: nl | n, vc lol klglop ; and Allll: lithium, the reaction lroplate at the temperature of the kitill); reaction} l; olmete "i, Vyho; 66L. T.ll. 2 5-2): S. And p and m R 26 N- (, 2-Д-Л-1л л: г- 2, 5-лчх: 1ор феп1 ;. in) .v жс - phenyl-prolyl) -rollolls ;;. Repeat lrms i e T .1l difference, lto ispo: 1b coziness amide 2-am; 1 lo-3, S-d; chlorine-N- (3-4-meth (lei-feiil-l; and) L l:) -M-1 1 ) ogilfel lukeuskl kieloch s i alum:.) lsl-, lrllem 1e1po ip (3, .1 t at T1 hlle 1tutnipl gl; -: ration smekl; Maelo. Iihj: -: ex 6 IR SECTOR (methyl lhlor L;;. E: N11 3390 + 3490 Ol1;., I .: 2800. UV-el lgl (-Tall) /..... with 343 (0, i3) 380 (2..0-; 30i30O.t), i: and m el 2. N ;-( 2 ---.- d ill-3, 3-d-chloro-Be lyl-ethyl) N (Zsl-fELL-lroli;) -gprylmi ;; . Polt-o'r Lrimer 1 e 1L; ) az-l1pel. lt Slöngнгng-amide 4-ami;) - 3, p-llllls; p-K- (3, 4-Mei (i.e., read, lr; l; (: -m) ekdi ;. at L ml., ll-re) lll: ll: t) sa Kiuioiinon dare. Ma.: L ;, lykhol, 707, P -el: ktr (m1-ti; il1: -l1S1ri.l), e - i: N11, 3,590 + 3490 .; SWAp; 2830, N-Alkl 2800. UV spectrum (ethanol) L max j 243 (0.13); 280 (0.04); 300 (0.04), EXAMPLE 28. N- (2-4-Lmill-3, fepyl-grogp-1l) -2-propidam. Example 1 is repeated, with the same scheme as that used by ami;:, 4-ami1 O-3,5-di-chloro-H- (3-4-methoxy-feiyl-propyl) -H-2-prop1-1L-phenuidel cioi acid: and lithium aluminum hydride, the reaction being carried out at the boiling point of the reaction mixture. Butter; yield 68%. IR spectrum (methylene chloride), cm: NH 3390 + 3490; OSI 3 2830. UV-specto (ethanol) max im 243 (0.13), 280 (0.04), 300 (0.04). Example 29. 1-4-Amino-3-cyano-5-fluoro-phenyl-2-H- (4-4-methoxy-phenyl-butyl) -methylaminoJ-ethanol. Example 1 is repeated with the difference that, / I „« // that 4-amino-3-cyan 5 -fluoro-2- M- (4-4-methoxy-phenyl-butyl) methylamino-acetophenone and sodium borohydride are used in 80% methanol. Oil, 25% yield. IR spectrum (methylene chloride), cm: OH 3590, NH 3400 + 3490; N-alkyl 2800; AXIS 2830; Aliphat. C 2850 + 2930; CSN 2210, 1635. UV spectrum (ethanol) A «axi 241 (0.27), 280 (0.07), 320 (0.14). Example 30. Racemates A and B are 1-4-amino-3, 5-dichloro-phenyl-2-N- (3-4-hydroxy-phenyl-1-methyl-propyl) -methyl-1-ethanol. 36 g of 1-4-amino-3, 5-dichloro-phenyl-2-rN- (3-4-OKCi-phenyl-1-methyl-propyl) -methylamino-ethanol (1: 1 mixture of diaste romeric racemates A and B ) is dissolved in ether and mixed with 0.5 eq 3 and hydrogen chloride in ether. The resulting crude crystallization product of the racemate A hydrochloride is first recrystallized from isopropanol, then twice by dissolving in a large amount of methanol and by subsequent evaporation until crystallization begins. T. pl. hydrochloride 248-249 0 (decomposition). Exit 35%. The mother solution of isopropanol is evaporated and partitioned between simple ether and 2N ammonia. The residue of the dried organic phase is purified by chromatography on silica gel with a large network of grains of 0.015-0.025 nm using a mixture of ether and methanol (10: 1) as eluent. The crystalline residue is recrystallized and a large amount of ether by concentration at boiling point. M.p. 128-131 C. Yield 18%. g; ectr (CDC1, / CDOD), ppm CH-CH2-SP-CH35, 61 ch-CH-CH-CH-61 CH 1 -CH N-CH N-CH2 Example 31. 1- (4- Amino-3,5-dichloro-phenyl) (4-hydroxy-phenyl) -propyl-anino (-ethanol. Example 3 is repeated, with the difference that 4-amino-3, 5 -dich. Por-2- | (4-hydroxy-NILE) -propyl j-amiHoV-acetophenone and sodium borohydride in aqueous tetrahydrofuran. Oil, yield 36%. IR spectrum (KVg), cm: OH, CN „33003600, aroma. 1615. UV spectrum (ethanol + KOH) 0 ((4, nm: 244 (0.26), 299 (0.08). Example 32. 1-4-Amn o-3,5-dichloro-phenyl-2-N- (3 -4-chlorophenyl-propyl) -amino} -ethanol. Example 3 is repeated with the difference that 4-amino-3,5-dichloro-2-y- (3-4-chloro-phenyl-pr opil) -amino1-acetophenone and sodium borpzdrid in aqueous tetrahydrofuran. Yield 32%, mp 103-106 ° C. Example 33. 1-4-Amino-3,5-dichlorophenyl-2-H- (3 -4-hydroxy-phenyl-1; -methyl-propyl) -isopropylamino-ethanol. Example 3 is repeated with the difference that 1 using 4-amino 3, 5 -dix JIop-2-GN- (3-4 oxy Fe il-1-methyl-propyl) -isopropylamino acetopheno and sodium borohydride. Oil, yield 28%. Found,%: C 61.07; And 6.86, cf 16.67; N 6.53. Calculated,%: C 61.31; H 6.86, Ci 17.24 N 6.81. Example 34. 1-4-Amino-3, 5-dichtoro-phenyl-2-M- (3-4-hydroxy-phenyl-1-methyl-propyl) -ethylamino-ethanol. Example 3 is repeated with the difference that the 4-amino-3, 5-dichloro-2-N- (3-4-hydroxy-phenyl-1-methyl-propyl) -ethylamino-acetophenone and sodium borohydride are used. Oil, yield 30%. Found,%: C 60.45; H 6.76; C1 17.70; N 6.86. Calculated,%: C 60.45; H 6.60; C1 17.85-, N 7.05. Example 35, 1-4-Metsh1amino-3, 5-dichloro-phenyl-2-s- (3-4-hydroxy-fega-1-methyl-propyl) -methylamino-T-ethanol.
    lCjB; 4 pHroT example) with IXB EFF) -; tsey that use - to-to-p-plp; , 5 - dnhlor-2-Hm- (L- - loc (: n-b. Hyyl 1 i if tyl 1 pO11)) methyl amine o I; h () f (: cn and borgchdrp ;;,; ghri „Mat: .4 (; ojo, h P; foam. l: (: 60. 68, Р h -:::
    1 I-i e I) 16 --- 1 / P1eti.1: am; io-3,; -dch: lo 1- (- - (- m-n n; -pheny--N CT; ui- nno ;; i: i) Mt: Til Finp-ztaiol.
    Poitor kut (njMiMt-r); g: -o pl-sitij ;;; :: that isp (5L), -; y1ot 4 -L. and etipamine :: - 5.,
     R
    5 -DIH.LSP1 h; -I N- (5 A-hydroxy-free | P: g- i -; i: til-propyl j-years laminins | -metskbspm
    Nl51D (M1G.:: C 6,; I i: C: 1 ,, п (: N Calculated), / l C m, 1;; ii .JUS
    C1 i 7. N „„ And i, And p and. I er J 7., Racemate L m 1-4-aMMHo-ij, tian-T-- bTop-bnH; i; v-2 - v - ( 1 st: lgl-4-hydroxy-f (T (; L-pr: L; -, p) - g-tilamSHO - tano. A
    Repeat yu and tims- with L: ;;: -l; L: 1 (::
    that ISL10L1L; LOT -. FHHC-l, luch-
    (pTOji J - IN - (i --Mi.-Tii: 5-: OKi .: l; bi-: il; -propyl) -stilamt-thio -ltuyloNchlp-l borpryhril iatrkp ,, IolukL: ;; -: Lll: diastsroomerplh ralolz gslg; l: .zls / .- lao-, posrsd1 ;; li) g ,; chromacho-rafsh; ma KCii not (Si.0o ° methylah; l-c ;; meT: L; glg, :: centri; o; a1ggni: l l l i
    Rapomat A,
    T. iTJ. 1 61- If:; C H |,; l; l: 7 7..
    (; -5 {Нг С1Л ктр (; р -li; -l / -: il ;, -l / -OKViCb). Л.;:..
    Racemate B.
    M.p. 92-98 C, Out; C-NMR spectrum (d,; -dimethyl; sid), h / m - 1No; Clii
    12
    9H, -SI-C1U-CH; I-a-.111
    .and; pKi-iHueK
    -: l ;;: g. ; -i:,; dr; other; p; 1l ,, snug;
      ; ::. A.:: .r-- ;. a-and temlrratur kipenig p -accident (. Oil., gp.: NK
    g; gene chloride) J; -. ojj) I ..... .
    - j. iOO
    1DROCHLORINE;
    70r-feiil-g; p
    G f I ..
       - - - to;: g:; 0; 1-1 - :: ro: i :)
    Example 1 is repeated with the difference that Bt-aNoiHo-S, 5-dichloro-phenyl-N- (3-4-methoxy-phenyl-propyl) -propionic acid amide is used and lithium aluminum hydride in absolute tetrahydrofuran, and the reaction is carried out at the boiling point of the reaction mixture. 75% yield. M.p. hydrochloride
    las-iAz c.
    Example 43. N- (2-A-amino-3 hydrochloride, 5-dichloro-phenyl-ethyl) -N- (4-4-methoxy-phenyl-butyl) -amine.
    Example 1 is repeated, with the difference that N- (2-4-amino-3,5-dichloro-phenyl-ethyl) -4-4-methoxy-phenyl-ethyl) -4-4-methoxy-phenyl-amide is used. butyric acid and lithium aluminum hydride in absolute tetrahydrofuran, and the reaction is carried out at the boiling point of the reaction mixture. Exit 63%. M.p. 186-189 ° C.
    Example 44. N- (2-4-amino-3, 3-dichloro-phenyl-ethyl-N- (3-4-chlorophenyl-propyl) -amine hydrochloride.
    Example 1 is repeated, with the difference that 4-amino-3,5-dichloro-N- (3-4-chloro-phenyl-propyl) -phenylacetic acid amide and aluminum hydrochloride in absolute tetrahydrofuran are used, and the reaction is carried out in the form of technical chemistry. boil the reaction mixture. Yield 70%. M.p. hydrochloride 186-190 ° C.
    Example 45 N- (2-4-AMHHo 3,5-dichloro-phenyl-ethyl) -Y- (4-4-methoxy-phenyl-butyl) -isopropyl o1H.
    Example 1 is repeated, with the difference that N- (2-4-aMiiHo-3,5-dichlorophenyl-ethyl) -N-H3onropyl-4-4-methoxy-phenylbutyric acid amide and lithium aluminum hydride are used in absolute tetrapvdrofuran wherein the reaction is carried out at the boiling point of the reaction mixture. Oil, yield 65%.
    IR spectrum (methylene chloride), cm: NH, 2 3390 + 3490; OSSN. 2850-22930; fragrance 1610.
    UV spectrum (ethanol) max 242 (0.12); 280 (shoulder, 0.04), - 301 (0.04).
    Example 46. K- (2-4-Amio-3,5-dichloro-phenyl-ethyl) -M- (1,1-dimethyl-3-4-hydroxy-phenyl-propyl) -methylamine.
    To a solution of 3 g (0.0075 mol) of 1-4-amino-3, 5-dichl or-fe NIL (2,1- .iiiMO; LIL of 3-4-oxy-phenyl-propyl) -metheyl Jlamino-ethanol in 12 ml triperoxonane acid with stirring
    at -10 ° C, 1.8 ml (0.018 mol) of pyridine-borane is added dropwise. After removing the oxidation, the reaction solution is heated to room temperature for 30 minutes and then heated in a water bath for 60 minutes. After evaporation of trifluoroacetic acid at 30 ° C under vacuum, the residue is mixed with 40 ml of 2N. After cooling, the reaction mixture is carefully acidified with concentrated hydrochloric acid, mixed with concentrated ammonia until alkaline, and then extracted 2 times with 73 ml of ether each time. The obtained ether extracts are washed twice, each time with 30 ml of water, after the compound is dried over magnesium sulfate and concentrated to dryness under vacuum. The residue is pre-purified on silica gel using a mixture of methylene chloride and methanol (2: 1) as eluent. Additional purification is carried out on alumina (neutral, degree of activity III). As an eluent, ether and n hexane were used 2: 1. The resulting oily residue crystallizes after a short time. Yield 58%. M.p. 122-124 0.
    Example 47 H- (2-4-amino-3, 5-dichloro-phenyl-ethyl) -M- (3-4-hydroxy-phen-1-methyl-propyl) -ethylamine.
    Example 45 is repeated, with the difference that 4-alumina-2-bromo-3, 3-dichloro-acetophenone, H- (3-4-ox-phenyl-1-methyl-propyl) -ethylamine, sodium carbonate in aqueous tetrahydrofuran. Alumina 1 (neutral, degree of activity III) is used for cleaning. Ether and petroleum ether 2: 1 were used as eluent. Oil, yield 56%.
    IR spectrum (methylene chloro-1), cm: OH 3590; MT 2 3480 + 3390; СН ,, С1Ц 2960 + 2930 + 2860; Y-Alk1sh 2810; 1585 + 1510 + 1485.,
    UV spectrum (ethanol)): c 241 (shoulder, 0.28), 280 - 3023 (0.08)
    UV spectrum (ethanol-con) Lmax 241 (0.56), 298 (0.17).
    Example 48. 1-4-Amino-3,3-dichloro-fensch-1-2-M- (1,1-dimethyl-3-4-hydroxy-phenyl-propyl) -methylamino-ethanol.
    P ov t about r p P r and MO -; i
    3-4-oxn-fsnil-T ropil t Me; sila 1-ui and altric carbonate .ri; .nj G o-gs -; n outgoing slug, which is)) 1y ascended on a sodium boggypl / ohm in water) e ragi; fofu:; ake. iredwai: body and supplement should be carried out on silica gel. A simple offpr and tetrahydrofuran are used as alumina alum.: 1 - a, t ;; also meth:; - lenhlori / and methanol and cshg. -Entated ammonia 30: 1: 0 1 T, il i 5-1 58 Exit | 7l
    PRI and eR - (9, 1-4-Amio-3,:;; dikhdor feiil-2-N (1 1-limoti.g-Z-- -oxn-frnil-prni .g: 1 -mi HI i --- and what:
    Repeat sweat g; pH1.te 3 with fuels and lubricants and m. That uses from 4-amino; i 5 -dixJ (nz acetopheneni. N, -dim mil-3-4-ox-phenyl-proylamine and cap:) o-sodium sodium for the preparation; nt of the starting product, which is iiiVuuip-aioT but (folding of the arm; 1 ; reed oi sodium: nodnogo tetrahydrofuranp;
    and additional purification of pOH (sidicagde, In kg cheste tlyusn) .; use a mixture of i:; t lenlochloride me-: Lnadogichi (1 pRi 1 pd lb m TTpitKiejiar-; get the following e;) edmnenp;
    1 4-Amnio-3 5 5-dik.og) -feii.1: -2- N - (3-4-feto cn-feln -th (.; T i ;; - io;: 4; ; ii, -methyl ;; mino -3T, i Ko.i, lacjr ;: li-ijci:
    -, a ggt
    3 b /;, „
    IR- (L1ektr (methi. Anhloride) ciOEI 3300-3500 (; J; H;: VOK.O, -the same., NH, CH ,,: 950, uO: 2830, N-aJHCHJi 2800, 1580, ;-); 01485,; C C + KH2 leformation; c20
    UV spectrum (ethanol) 7,, ..,. „, -M: 244 (0.27); 280 (0.08); , 08)
    1-4-Amino-3, 5-dmchlor-FSN -: g-3- i. (1 5 I di setil-3 4-ietok:; - Phen ii (-progyl) -ethanol - Maf;: i - i Emkhod327 ..
    PC spectrum (meth. Aenchloride). cm: OH 3600, NH, 3390 + 3490 / CH. 2860+ + 2960 OCHO, 2830, 1580 + 1620.
    UV spectrum (ethanol). la, , nk; 243 (0.23), 280 (0.08). HHSG (0.08)
    1-4 Amino-3 5 5-dnne: 1phenyl - 2 ™ j N- (1S 1-dimethyl-3-4-methoxy-fe1-1i, p-proni-sh) -methylamino-ethanol, oil, Yield 34%.
    will find) ; С i 1, GZ ;. n 6. 99:
    C-: 2S; kb, b.
    Rynk :: and n (1,. (I 61,. I L.Yam -1 24; N 6.81.
    Hydrs) chloride 1, 5-d-x; tor fe; {id-x - (N 3-fenn.p drogni, 141): anola, i27, T, al. i8-i8i ° C (pa zpogs (and- :().
    1-4-Am1 type 1 - neither; -, -; -ф-г (р-, 1) Р1; :::; - ;; (t-il- - :.); with H-fs NIL PID) -motyla1 1I (o - aiioj J oil. Yield 30%.
    IR spectrum (m (.; G 1L P1;: 1o; 1 ;;), cm; N; i; - 3400 35jiy O-Cm, ..., YAZO; vl; -,;, -, 280-; / 2М;. I 5 К: С-О + N11, de (Bormad 1 п20.
    nor / iaMiiHoj - ttaiol, oil. Out; hZ,
    liK-cr-; eKTp (sword-; 1Л; l: x: 1soid). () 3580; iNtU 3390 + 3480: aliphatic ;; ,, 850 + 2930; O -;.: 16 P.
    UV spectrum (mganol), am: 243 C0j26), 333 (D) 08). 3 () i fO.OB).
    UV-spectrum (-ethanol + KOI) A „,;. / „(0.47); 298 (0. 19).
    - (2-4-Lmi o-3 J, 3-dichloro-fogi. Ilg-N- (4-D - m (. Xy-phenyl-but-; l) IR-sp) tr l-Yuppe nx / yuri :;), cg; i - b 2Я60-3910., ar.-mat, C-0; 610
    J. P2-.h-Lmino-3, g-dichloro-fe H: .l-U il) - i 1, J-4-XJJOp- (Се Hj-fJ -IpOH; 1 i - and ЧО -: lamin , oil. B; ixoj; 23l,
    IR spectrum) methylene chloride,), cm: UN, ,, 3390 + 5480, aroit OO 615.
    UV-sl-K; -r Gethanol) .. s, yy: - KO; 3), 300 (0.05).
    idrokhlori ;; N - (methyl 2-4-amino J, 5-lihps; p-fe11yl-ethyl) -X- (3-4 -: etoksn-fensht-P)) - amine. Yield 62%, ,, T,;: l. Mr. hydrochloride 193-195 C.
    Hydrochloride 1-4-a of shno-3,5-dichloropen-2-phenyl-2- (M-1-methyl-3-phenyl-nropyl-methylamino) ethanol .. Yield 36%. Oily scrod chloride,
    IR spectrum (methylene chloride),
    NH, 3390 + 3490; NH 2300-2400; Olf 3580. vcJ) -cneKTp (ethanol). , im: Hydrochloride 1-4-lmino-3, s-dnchlor -feiyl-2- (N-1-methyl-3-phenyl-propnl-methylamino) -ethanol. Yield 70%. M.p. hydrochloride 170-173 ° C. Hydrochloride 1-4-amino-3, 5-dichloro-phenyl-2 Hm-) -methyl-3-phenyl-propyl-propylamino) -ethanol. Yield 64%. Oily hydrochloride. IR spectrum (methylene chloride), cm: NH 3390 + 3490; NH 2300-2400; OH 35 +3680. UV spectrum (ethanol), nm: 245 (0.12), 302 (0.03). N- (2-4-amino-3, 5-dichloro-phenyl-ethyl) -N-3-phenyl-propyl-n-propylamine hydrochloride. Yield 65%. Oils nista hydrochloride. IR spectrum (methylene chloride), cm: NH 3390 + 3490; NH® 2300-2400; OH 360 +3650. UV spectrum (ethanol), im: 24 (0.17), 302 (0.05). Hydrochloride 1-4-a№1no-3-cya1-5-fluoro-phenyl-2-HK- (3-4-methoxy-phenyl-propyl) -ethylamino-ethanol. Oily hydrochloride. Yield 19%. IR spectrum (methi; 1 enchloride), cm: NH 3390 + 3490; NH® 2300-2500; CN 22 OH 3590 + 3680. UV spectrum (ethanol), nm: 248 (0.11), 280 (0.03), 320 (0.06). 1-4-Amino-3, 5-dichloro-phenyl-2- (Y-1-methyl-3-phenyl-prog1-ethylamino) -ethanol, oil. Yield 51%. IR spectrum (methylene chloride), cm: Chl 3390 + 3490. UV spectrum (ethanol) Adds; 245 (0.13), 300 (0.03). 1-4-Dimethylamino-3, 5-dichlorophenyl, -2- (N-3-phenyl-1-methyl-propyl-methylamino) -ethanol, oil. Yield 39%. / IR spectrum (methylene chloride), OH 3600 + 3680, N-alkyl 2800. UV spectrum (ethanol) 275 nm (0.03). 1-4-ANmHo-3,5-dichlorophenyl-2- N- (3-3-methoxy-phenyl-propyl) -aMHHoJ-ethanol. Yield 65%. M.p. 124 C. N- (2-4-Amino-3, 5-dichloro-phenyl-ethyl) -N-3-phenyl-1-methyl-propyl-methylamine. Yield 61%. Oily hydrochloride.J IR s:; ECG (methylene chloride), CG, 3V3 + 3490, SI 2 2930. UV spectrum (ethanol) TV, nm: 243 (0.12), 300 (0.04). N- (2-4-Lmino-3, 5-dichloro-phenyl-ethyl) -N-3-phenyl-1-methyl-propyl-n-propylamine. Exit 63%. Oil nyst pshrokhlorid. IR spectrum (methylene chloride), cm: NH2 3390 + 3490, CH 2930. UV spectrum (ethanol) 7 mots nm: 245 (0.11), 300 (0.04). New connections. L. 1-4-Amino-3,5-dichloro-phenyl-2-J- (3-4-methoxy-phenyl-propyl) -amino1-ethanol. B. 1-4-Amino-3-cyano-5-fluoro-phenyl-2-N- (3-4-methoxy-phenyl-propyl) methylamino-ethanol. B. Hydrochloride of 1-4-amino-3, 5-dichl or-pene or l-2- (L-3-phenyl-pr opil-2-propylamino) ethanol. G. 1-4-Amino-3, 5-dichlorophenyl-2- N- (3-4-hydroxy-phenyl-1-methyl-propyl) methylamino-ethanol. D. 1-4-A lino-3,5-dichloro-phenyl-2-N- (1, 1-dimethyl-3-4-hydroxy-phenyl-propyl) -amino1-ethanol. E. Hydrochloride 1-4-amnno-3,5-dichloro-phenyl-2- (N-1-methyl-3-phenyl-propyl-propylamino) -ethanol. G. 1-4-Dimethylamino-3,5-dichlorophenyl-2- (N-1-methyl-3-phenyl-propyl-methylamino) -ethanol. 3. 1-4-Amino-3, 5-dichloro-phenyl-2- (N-1-methyl-3-phenyl-propyl-ethylamino) -ethanol. I. 1-4-Amino-3-cyano-5-fluorophenyl-2-N- (3-4-methoxy-phenyl-propyl) ethylamino-ethanol hydrochloride. K. 1-4-Amino-3, 5-dichloro-fennl-2-N- (3-4-hydroxy-phenyl-1-methyl-propyl) -allylamino-ethanol. L. 1-4-A DiHO-3,5-dn-chloro-phenyl-2-N-I, 1-dimethyl-3- (4-methox-phenyl-propyl) -amino-ethanol. M. 1-4-Amino-3-cyano-5-fluoro-phenyl-2- {N- (2-3,4-dimethoxy-mostch-ethyl) -ethipamino-Z-ethanol. I. 1-4-A shno-3-cyan-5-fluoro-phenyl-2 Gm- (1-methyl-3-4-hydroxy-phenyl-pro-1-pi. P) -aMHHoJ-ethanol. 0. Hydrochloride 1-4-amino-3, 5-dich, or-phenyl-2- (N-3-phenyl-propyl-amino) -ethanol. P. Hydrochloride N- (1-methyl-2-4-amino-3, 5-dichloro-phenyl-ethyl) -H- (3-4-methoxy-phenyl-quenched) -amnna. R. H- (2-4-Amino-3,5-dichloro-fennethyl) -M- (3-4-chlorophenyl-propyl) -ioropylamine.
    C, N- (3-4-Chloro-phenyl-propyl) -N- (2-3,5-dichloro-4-isopropyl-amino-phen Ш 1 -e t yl) -and 3 ODA o p il i n i The known compound 1- (4-amino-3, 5-dibromophenyl) -2- (N-benzylamino) ethanol hydrochloride was tested for their effect on blood pressure as follows.
     and female cats weighing 2-4 kg are anesthetized with the pentobarbital dacha in the form of sodium salt (40 mg / kg intraperitoneally) and the pentobarbital is continuously infused in the form of sodium cojui to maintain anesthesia. The stomach is spontaneously.
    Body temperature G1odd; holding 38 ° C with the help of e: 1ectropod, ears and thermostat. The pressure in the left ventricle of the heart was measured by means of a pressure sensor inserted through the right aorta into the left ventricle of the heart, and the pressure signal continuously measured; The rate of increase in pressure p / was made using a diffuser.
    In addition, the half-life and oral toxicity in mice were also determined (each test compound is pressed 3 times in size).
    The results of the experiment; 1 given in the table.
     Compound I Twice | Period
    Continuation of the table
    Comparison of the data in the table of the swine body. That the new piperidine derivatives exhibit better properties than the known compound-.
    权利要求:
    Claims (1)
    [1]
    A method of producing phenylalkylamine derivatives of the general formula
    Rg is a hydrogen or chlorine atom, hydroxyl or methoxy;
    R - a hydrogen atom or methoxy ',
    E is n-propylene unsubstituted or substituted by one or two methyl groups, or their salts, characterized in that the compound is of the general form, where R, R ^, R. pR s and B have the indicated meanings, X is a group of the general formula ω
    where R ( is an amino group, an alkylamino or dialkylamino group with the number of carbon atoms 1-3 in the alkyl part;
    R, - atom halogen; R. - atom chlorine or cyano group; R 4 - atom hydrogen methyl; R 5 atom hydrogen metal ‘
    A is a methylene or oxymethylene group,
    B is a group of general formula k,
    -CO-CH-,
    -sn g -so- ;
    OH Its
    I I-sn-sngde has the indicated value, is subjected to reduction with a complex metal hydride or pyridinoborane, followed by isolation of the target product in free form or in the form of a salt.
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    同族专利:
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    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    DE1618007A1|1967-05-09|1970-10-29|Thomae Gmbh Dr K|Process for the production of new amino-monohalophenylaethanolamines|
    NL176168C|1972-12-18|1985-03-01|Thomae Gmbh Dr K|PROCESS FOR PREPARING RESPECTIVELY MANUFACTURE OF A PHARMACEUTICAL PREPARATION AND PROCESS FOR PREPARING USE THEREFORE NEW SUBSTITUTED 1- -2-AMINO-ETHANOL DERIVATIC, ATTENTLY ANTISOL, AN ANTISEROL IN PARTICULAR, HAVE BETAŸ2-MIMETIC AND / OR BETAŸ1-BLOCKING EFFECT.|
    DE2351281C3|1973-10-12|1981-07-30|Dr. Karl Thomae Gmbh, 7950 Biberach|Aminophenylethanolamine derivatives, their production and use|
    GB1523974A|1975-02-05|1978-09-06|Yamanouchi Pharma Co Ltd|4-substituted amino- -aminomethylbenzyl alcohol derivatives|
    JPS5740819B2|1975-02-05|1982-08-30|
    EP0006961A1|1978-02-21|1980-01-23|Sandoz Ag|New phenylethylamines, process for their preparation, and pharmaceutical compositions containing them|
    IL57670A|1978-07-03|1982-11-30|Lilly Co Eli|Phenethanolamines,their preparation and pharmaceutical formulations comprising them|US4720586A|1983-12-06|1988-01-19|Fisons, Plc|Substituted 3,4-dihydroxy-phenylethylamino compounds|
    GB8419963D0|1984-08-06|1984-09-12|Lundbeck & Co As H|Intermediate compound and method|
    GB8426191D0|1984-10-17|1984-11-21|Glaxo Holdings Ltd|Chemical compounds|
    US4943591A|1984-10-17|1990-07-24|Glaxo Group Limited|Dichloroaniline derivatives|
    GB8603475D0|1986-02-12|1986-03-19|Glaxo Group Ltd|Chemical compounds|
    EP0278727A3|1987-02-10|1990-03-14|Glaxo Group Limited|1--2-ethanol derivatives and their use in the treatment of respiratory disease|
    GB8703007D0|1987-02-10|1987-03-18|Glaxo Group Ltd|Chemical compounds|
    US4906645A|1988-09-12|1990-03-06|Merck & Co., Inc.|Pyridyl aminoethanol compounds with growth promotion and an increase in feed efficiency|
    DE4028398A1|1990-09-07|1992-03-12|Thomae Gmbh Dr K|PHENYLETHANOLAMINES, MEDICAMENTS CONTAINING THESE COMPOUNDS AND METHOD FOR THE PRODUCTION THEREOF|
    US5495046A|1991-01-04|1996-02-27|Taisho Pharmaceutical Co., Ltd.|Alkoxyphenylalkylamine derivatives|
    WO2010059711A1|2008-11-18|2010-05-27|Wisconsin Alumni Research Foundation|Sigma-1 receptor ligands and methods of use|
    GB201208775D0|2012-05-18|2012-07-04|Uni I Oslo|Chemical compounds|
    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    DE3046465|1980-12-10|
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