CN101735229A - Tetrahydroisoquinoline compounds and preparation method and application thereof - Google Patents

Tetrahydroisoquinoline compounds and preparation method and application thereof Download PDF

Info

Publication number
CN101735229A
CN101735229A CN200910248728A CN200910248728A CN101735229A CN 101735229 A CN101735229 A CN 101735229A CN 200910248728 A CN200910248728 A CN 200910248728A CN 200910248728 A CN200910248728 A CN 200910248728A CN 101735229 A CN101735229 A CN 101735229A
Authority
CN
China
Prior art keywords
preparation
compound
acid
salt
target compound
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
CN200910248728A
Other languages
Chinese (zh)
Inventor
许佑君
魏秀岩
从俊杰
张青扬
倪积智
林禄清
肖和平
韩福庆
王哲
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Shenyang Pharmaceutical University
Original Assignee
Shenyang Pharmaceutical University
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Shenyang Pharmaceutical University filed Critical Shenyang Pharmaceutical University
Priority to CN200910248728A priority Critical patent/CN101735229A/en
Publication of CN101735229A publication Critical patent/CN101735229A/en
Priority to PCT/CN2010/002161 priority patent/WO2011075957A1/en
Priority to CN201010621249.6A priority patent/CN102134245B/en
Pending legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/02—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines
    • C07D217/04—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines with hydrocarbon or substituted hydrocarbon radicals attached to the ring nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/22—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the nitrogen-containing ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The invention belongs to the technical field of medicament synthesis and in particular relates to synthesis of tetrahydroisoquinoline compounds and initial application of the tetrahydroisoquinoline compounds in inhibiting tumor cell proliferation. Through the modification of a structure of natural (-)-alpha-(1R,9S)-narcotine, a series of novel tetrahydroisoquinoline compounds (I) are synthesized. Through the screening of anti-tumor activity in vitro, the novel tetrahydroisoquinoline compounds have remarkable effect of inhibiting the tumor cell proliferation activity and can be further developed into a novel anti-tumor medicament.

Description

Tetrahydroisoquinolicompounds compounds and its production and use
Technical field
The invention belongs to the synthetic field of medicine, relate to tetrahydroisoquinolicompounds compounds and preparation method thereof, and the first Application of this compounds aspect the inhibition tumor cell proliferation.At the active research of inhibition tumor cell proliferation of these compounds, be the present invention's initiative, this research is significant to the exploitation new type antineoplastic medicine.
Background technology
(-)-α-(3S, 5R)-Noscapine belongs to the opiates alkaloid, English name (-)-α-(3S, 5R)-Noscapine or Narcotine, molecular formula C 22H 23NO 7, chemical name (-)-(3S, 5R)-6,7-dimethoxy-3-(5,6,7,8-tetrahydrochysene-4-methoxyl group-6-methyl isophthalic acid ', 3 '-dioxole [4 ', 5 '-g]-the 5-isoquinolyl)-1 (3H)-isobenzofuranone, be classical antitussive medicine, it is low to have toxic side effect, better tolerance, characteristics such as safety range is wide.Simultaneously, Noscapine can be used for treating cerebral apoplexy and oedema.
Figure G2009102487285D00011
1998 Joshi seminar (Joshi et al., Proc Natl Acad Sci USA, 1998,95,1601) discover that Noscapine has the good resistance tumor promotion.Noscapine can stop cell mitogen the phase in M, inducing apoptosis of tumour cell.Experiment in vitro shows, to the IC of t cell lymphoma cell E.G7-OVA propagation inhibition 50Value is 10 μ mol/L (Ke et al., Cancer Immunol Immunother, 2000,49,217), to the IC of human cervical carcinoma cell Hela propagation inhibition 50Value is 25 μ mol/L (Joshi et al., Proc Natl Acad Sci USA, 1998,95,1601).The mouse of implanting human breast cancer cell MAF-7 is compared with control group after accepting Noscapine (120mg/kg dosage) 3 weeks of administration, and tumor control rate is 80%, and check pathological section is not found tangible tissue toxicity.Jaren etc. (Jaren et al., ClinCancer Res, 2004,10,5187) find that with the immunodeficient mouse model experiment Noscapine reaches 85% to the melanomatous inhibiting rate of B16LS9, are 78% to C6 neuroglial tumor cell inhibiting rate.HPLC detects in the full brain homogenate centrifugal of the mouse supernatant liquor and contains Noscapine, and not only oral absorption is good to show Noscapine, also can pass through hemato encephalic barrier.
Animal experiment shows, Noscapine does not all have any overt toxicity (Ebrahimi et al., Acta Physiol Hung, 2003 to tissues such as the heart, spleen, kidney, duodenum, thymus gland, blood and marrow or organ with various dose, different modes of administration, 90,147).Noscapine is to the LD of mouse 50Value can detect temporary transient neurotoxicity (Landen et al., Cancer Res, 2002,62,4109) for (602 ± 31) mg/kg when 90mg/kg.Humoral immunization and cellular immunization are not had the obvious suppression effect yet, only mucous membrane of small intestine is had gentle pungency, but do not cause tangible epithelial cell disappearance, faint hepatotoxicity (Ebrahimi et al., Acta Physiol Hung, 2003 are arranged when heavy dose of, 90,147).
Different with the mechanism of action of taxol and vinca medicine, though Noscapine acts on tubulin, but do not show the polymerization that promotes or suppress microtubule, do not change the polymer and the monomeric ratio of tubulin yet, but with stoichiometric ratio (Noscapine molecule: tubulin dimer=0.95 ± 0.02) combine with tubulin, change " the mechanics unstable " of microtubule, cause microtubule to be in the time lengthening of attenuation state (this state microtubule length is constant).Microtubule is in attenuation state and will directly causes the tension force between the sister chromosome kinetochore to disappear, and the isolating moment of sister chromosome is postponed, and cell is blocked at the M phase of m period.Thereby can induce the kinds of tumor cells apoptosis, comprising taxol being produced chemical sproof tumour cell (Zhou et al., J BiolChem, 2002,277,39777).
Classical microtubule class medicine influences the fissional while by promoting or suppressing microtubule polymerization, has also had influence on other functions of microtubule, causes side effects such as neural widely and blood.And Noscapine only disturbs the microtubule dynamic instability, and does not change the polymer and the monomeric ratio of tubulin, does not also destroy microtubule " polymerization-depolymerization dynamic circulation " mechanism, infers that thus Noscapine is very little for the cell nontoxicity or the toxicity of proper splitting.
As the medicine of leukemia, lymphatic cancer, Noscapine has entered the first phase clinical study stage.
In addition, Noscapine also has effect of flesh pine and angst resistance effect, certain analgesic activities.
C-9 ' the position that the structural modification of Noscapine and the research of the anti-tumor activity of analogue thereof also have report, the position of modification mainly to concentrate on C-1 position, C-7 position and the tetrahydroisoquinoline ring of isobenzofuranone (is the R of patent of the present invention 5The position).
(1) C-9 ' position (R 5The position) modification on: C-9 ' position H atom is with halogen such as F, Cl or Br etc. substitute, the anti-tumor activity of gained compound increases (Verma et al., Bioorg Med Chem, 2006,14,6733), wherein the chloro thing is the strongest to people's glioma brain tumour U87 series cell activity, bromo-derivative demonstrates tumor promotion (the Zhou et al. of very strong ovarian cancer resistance cell, MolPharmacol, 2003,63,799), the cyclo other compounds that fluorine replaces shows the anti-breast cancer activity stronger than Noscapine (Anejaet al., Bioorg Med Chem, 2006,14,8352).These halo derivatives oral administration biaavailability height are not found the toxicity to tissues such as the heart, spleen, kidney, duodenum, thymus gland, blood and marrow.And the nitration thing of this position has very strong activity (Aneja et al., Mol Pharmacol, 2006,69,1801) to ovarian cancer, T-Cell lymphoma.To the tumour cell of taxol resistance, these compounds are all effective.
(2) to the modification of C-1 position: the parent nucleus isobenzofuranone is replaced with the isobenzofuran structure, corresponding compound has than more firm tubulin binding ability of Noscapine and stronger anti-tumor activity, and tumour cell obviously reduces (Zhou etal. to its resistance, Cancer Chemother Pharmacol, 2005,55,461).
(3) to the modification of C-7 position: people attempt MeO with OH, SH, NH 2And replacement such as aryl, the gained compound still has tangible anti-tumor activity, but is not quite similar with the mechanism of action of Noscapine, and this compounds blocking-up cell mitogen is in the S phase, and the blocking-up rate can reach 65%.(Anderson?et?al.，J?Med?Chem，2005，48，2756)。
In sum, Noscapine and analogue thereof are novel microtubule series antineoplastic medicament, have active high, mechanism of action is unique, toxic side effect is little, oral absorption is good, can see through hemato encephalic barrier, and can with characteristics such as other drug drug combination, therefore caused investigators' keen interest in recent years.System carries out structural modification, this stronger compounds of searching effect, will be significant, and also lays the foundation for seeking the new antitumoral medicine.
Summary of the invention
Technical problem solved by the invention be by to natural (-)-α-(1R, 9S)-Noscapine carries out structure of modification, synthetic a series of tetrahydroisoquinolicompounds compounds (I, II, III, IV and V).By the anti tumor activity in vitro screening, found the active compound of many remarkable inhibition tumor cell proliferations.At the research of the tumor cell proliferation inhibition activity of these compounds, be the present invention's initiative, so research is significant to the exploitation new type antineoplastic medicine.
Another object of the present invention provides the preparation method of above-claimed cpd.
Novel tetrahydro isoquinoline compound of the present invention has the structure of following general formula (I, II, III, IV and V).
Figure G2009102487285D00021
Wherein: (a) R 1A kind of in expression hydrogen atom, 1～6 carbon straight chain and branched hydrocarbyl, tetrahydrofuran (THF)-2-base, different benzofuran ketone group or the substituted aryl alkyl;
(b) R 2Expression hydrogen atom, 1～6 carbon straight chain and branched hydrocarbyl ,-COOR 11,-CH 2COOR 11,-CH (CH 3) COOR 11Or-CH 2CH 2COOR 11, R wherein 11Be a kind of in 1～4 carbon straight chain and the branched hydrocarbyl;
(c) R 3Expression hydrogen atom, methyl, ethyl ,-COOR 11Or-CH 2COOR 11In a kind of, R wherein 11Be 1～4 carbon straight chain and branched hydrocarbyl;
(d) R 5～R 8A kind of in the substituting groups such as expression hydrogen atom, methoxyl group, oxyethyl group, hydroxyl, difluoro-methoxy, benzyloxy or 1～6 carbon straight chain and branched hydrocarbyl, wherein R 8Can be 1～4 carbon straight chain and branched alkoxy; When on the ring enough electron-donating groups being arranged, R 5～R 8Can partly replace for halogen; Or the consecutive position is with 1, and 3-dioxolane form links to each other as R 5With R 6, R 6With R 7, R 7With R 8For-OCH 2The O-substituting group;
(e) R ' 4～R ' 8A kind of in expression hydrogen atom, methoxyl group, oxyethyl group, hydroxyl, benzyloxy, difluoro-methoxy, hydroxyl methoxyl group, halogen, nitro or 1～6 carbon straight chain and the branched hydrocarbyl; Or the consecutive position is with 1, and 3-dioxolane form links to each other as R ' 4With R ' 5, R ' 5With R ' 6, R ' 6With R ' 7For-OCH 2The O-substituting group.n＝0～2；
(f) R 9A kind of in hydrogen atom, hydroxyl or the acyloxy of expression;
(g) R 10A kind of in expression hydrogen atom, methyl, ethyl, aryl, arylmethyl or the fragrant ethyl;
(h) organic acid of acceptable salt correspondence is a kind of in oxalic acid, succsinic acid, acetic acid, Succinic Acid, toxilic acid, fumaric acid or the tartrate, and mineral acid is a kind of in hydrochloric acid, Hydrogen bromide, hydroiodic acid HI, sulfuric acid or the phosphoric acid.
The preparation method of formula I type compound of the present invention such as Scheme 1: substituted carboxylic acid compounds VI or its acyl chlorides VII and aminated compounds VIII through condensing agent or the conventional method condensation that forms amido linkage, are obtained amides IX.The Bischler-Napieralski reaction takes place through processing such as phosphorus oxychloride in IX, generates corresponding imines (or enamine) compounds X.X reduces through routine, and especially reduction such as sodium borohydride or POTASSIUM BOROHYDRIDE promptly gets target compound Ia, or obtains salt formula target compound Ia with sour salify in organic solvents such as methyl alcohol, ethanol, THF, DME or ethyl acetate.
Target compound or its salt Ia are with aldehyde compound and HCOOH, NaBH such as formaldehyde, acetaldehyde, aryl formaldehyde 4, KBH 4, NaBH 3CN, KBH 3Reductive agent such as CN or DIBAL-H obtains target compound Ib, or obtain the salt Ib of target compound with sour salify in organic solvent such as methyl alcohol, ethanol, THF, DME or ethyl acetate after handling and carrying out hydrocarbylation; Or the direct hydrocarbylation of Ia is and R 2X reacts under alkaline condition, obtains target compound Ib, or obtains the salt Ib of target compound in organic solvents such as methyl alcohol, ethanol, THF, DME or ethyl acetate with sour salify, and the used alkali of this reaction is Et 3N, ( I-Pr) 2NEt, pyridine, NaHCO 3, KHCO 3, Na 2CO 3Or K 2CO 3, solvent for use is N, dinethylformamide, methylene dichloride, ethylene dichloride, chloroform, hexanaphthene, normal hexane, THF, DME or ethyl acetate.R 2Expression hydrogen atom, 1～6 carbon straight chain and branched hydrocarbyl ,-COOR 11,-CH 2COOR 11,-CH (CH 3) COOR 11Or-CH 2CH 2COOR 11In a kind of, R wherein 11Be 1～4 carbon straight chain and branched hydrocarbyl.
Target compound or its salt Ia and X (CH 2) mCOOR 11React under alkaline condition, obtain target compound Ic, or obtain the salt Ic of target compound with sour salify in organic solvents such as methyl alcohol, ethanol, THF, DME or ethyl acetate, wherein m=0～6 especially 0～2, R 11Be 1～4 carbon straight chain and branched hydrocarbyl.The used alkali of this reaction is Et 3N, ( I-Pr) 2NEt, pyridine, NaHCO 3, KHCO 3, Na 2CO 3Or K 2CO 3Deng, solvent for use is N, dinethylformamide, methylene dichloride, ethylene dichloride, chloroform, hexanaphthene, normal hexane, THF, DME or ethyl acetate.
Active sulphonate [the CH of target compound or its salt Ia and lactic acid or its ester 3(OSO 2R ') COOR 11, R '=Me, CF 3Or 4-MeC 6H 4] under alkaline condition, react, obtain target compound Id, or in organic solvents such as methyl alcohol, ethanol, THF, DME or ethyl acetate, obtain the salt Id of target compound, wherein R with sour salify 11Be 1～4 carbon straight chain and branched hydrocarbyl.The used alkali of this reaction is NaHCO 3, KHCO 3, Na 2CO 3, K 2CO 3, Et 3N, ( I-Pr) 2NEt or pyridine etc., solvent for use are methylene dichloride, ethylene dichloride, chloroform, hexanaphthene, normal hexane, THF, DME, N, dinethylformamide or ethyl acetate.
Formula II type compound of the present invention is by preparing as Scheme 2 methods: 1 (3H) that will replace-different benzofuran ketone-3-formic acid (XI) is processed into corresponding chloride compounds XII through chlorination reagent.XI or XII and the suitable aminated compounds VIII that replaces obtain amides XIII through condensing agent or the conventional method condensation that forms amido linkage.The Bischler-Napieralski reaction takes place through processing such as phosphorus oxychloride in XIII, generates corresponding imines (or enamine) compounds X VI.XVI reduces through routine, and especially reduction such as boron sodium oxide or POTASSIUM BOROHYDRIDE promptly gets target compound IIa, or in organic solvents such as methyl alcohol, ethanol, THF, DME or ethyl acetate with sour salify, obtain salt formula target compound IIa.
Target compound or its salt IIa reduction amination are promptly with aldehyde compound and HCOOH, NaBH such as formaldehyde, acetaldehyde, aryl formaldehyde 4, KBH 4, NaBH 3CN, KBH 3Reductive agent such as CN or DIBAL-H is handled and to be carried out hydrocarbylation and obtain target compound IIb, or in organic solvents such as methyl alcohol, ethanol, THF, DME or ethyl acetate with sour salify, obtain the salt IIb of target compound; Or the direct hydrocarbylation of IIa is and R 2X reacts under alkaline condition, obtains target compound IIb, or in organic solvents such as methyl alcohol, ethanol, THF, DME or ethyl acetate with sour salify, obtain the salt IIb of target compound.The used alkali of this reaction is NEt 3, ( I-Pr) 2NEt, pyridine, NaHCO 3, KHCO 3, Na 2CO 3Or K 2CO 3, solvent for use is N, dinethylformamide, methylene dichloride, ethylene dichloride, chloroform, hexanaphthene, normal hexane, THF, DME or ethyl acetate.R 2Expression hydrogen atom, 1～6 carbon straight chain and branched hydrocarbyl ,-COOR 11,-CH 2COOR 11,-CH (CH 3) COOR 11Or-CH 2CH 2COOR 11In a kind of, R wherein 11Be 1～4 carbon straight chain and branched hydrocarbyl.
Target compound or its salt IIa and X (CH 2) mCOOR 11Under alkaline condition, react, obtain target compound IIc, or in organic solvents such as methyl alcohol, ethanol, THF, DME or ethyl acetate with sour salify, obtain the salt IIc of target compound.Wherein m=0～6 especially 0～2, R 11Be 1～4 carbon straight chain and branched hydrocarbyl.The used alkali of this reaction is Et 3N, ( I-Pr) 2NEt, pyridine, NaHCO 3, KHCO 3, Na 2CO 3Or K 2CO 3Deng, solvent for use is N, dinethylformamide, methylene dichloride, ethylene dichloride, chloroform, hexanaphthene, normal hexane, THF, DME or ethyl acetate etc.
Target compound or its salt IIa and lactic acid or its active sulphonate [CH 3CH (OSO 2R ') COOR 11, R '=Me, CF 3, 4-MeC 6H 4Deng] under alkaline condition, react, obtain target compound IId or in organic solvents such as methyl alcohol, ethanol, THF, DME or ethyl acetate with sour salify, obtain the salt IId of target compound, R 11Be 1～4 carbon straight chain and branched hydrocarbyl.The used alkali of this reaction is NaHCO 3, KHCO 3, Na 2CO 3, K 2CO 3, Et 3N, ( I-Pr) 2NEt or pyridine, solvent for use are methylene dichloride, ethylene dichloride, chloroform, hexanaphthene, normal hexane, THF, DME, N, dinethylformamide or ethyl acetate.
Figure G2009102487285D00051
Formula III type compound of the present invention is by preparing as Scheme 3 methods: the aromatic acid (XV) that replaces is processed into corresponding chloride compounds XVI through chlorination reagent.XV or XVI and the suitable aminated compounds VIII that replaces obtain amides XVII through condensing agent or the conventional method condensation that forms amido linkage.The Bischler-Napieralski reaction takes place through processing such as phosphorus oxychloride in XIV, generates corresponding imines (or enamine) compounds X VIII.XVIII reduces through routine, especially sodium borohydride or POTASSIUM BOROHYDRIDE etc. the reduction promptly get target compound IIIa, or in organic solvents such as methyl alcohol, ethanol, THF, DME or ethyl acetate with sour salify, obtain salt formula target compound IIIa.R wherein " be hydrogen, methyl, ethyl, aryl, arylmethyl or fragrant ethyl.
Target compound or its salt IIIa are with aldehyde compound and HCOOH, NaBH such as formaldehyde, acetaldehyde, aryl formaldehyde 4, KBH 4, NaBH 3CN, KBH 3After reductive agent such as CN or DIBAL-H is handled and to be carried out hydrocarbylation, obtain target compound IIIb or, obtain the salt IIIb of target compound according to the salifying method of claim 3; Or the direct hydrocarbylation of IIIa is and R 2X reacts under alkaline condition, obtains target compound IIIb or according to the salifying method of claim 3, obtains the salt IIIb of target compound.The used alkali of this reaction is NEt 3, ( I-Pr) 2NEt, pyridine, NaHCO 3, KHCO 3, Na 2CO 3Or K 2CO 3, solvent for use is N, dinethylformamide, methylene dichloride, ethylene dichloride, chloroform, hexanaphthene, normal hexane, THF, DME or ethyl acetate.R 2Expression hydrogen atom, 1～6 carbon straight chain and branched hydrocarbyl ,-COOR 11,-CH 2COOR 11,-CH (CH 3) COOR 11Or-CH 2CH 2COOR 11In a kind of, R wherein 11Be 1～4 carbon straight chain and branched hydrocarbyl.
Target compound or its salt IIIa and X (CH 2) mCOOR 11React under alkaline condition, obtain target compound IIIc or according to the salifying method of claim 3, obtain the salt IIIc of target compound, wherein m=0～6 especially 0～2, R 11Be 1～4 carbon straight chain and branched hydrocarbyl.The used alkali of this reaction is Et 3N, ( I-Pr) 2NEt, pyridine, NaHCO 3, KHCO 3, Na 2CO 3Or K 2CO 3, solvent for use is N, dinethylformamide, methylene dichloride, ethylene dichloride, chloroform, hexanaphthene, normal hexane, THF, DME or ethyl acetate.
Active sulphonate [the CH of target compound or its salt IIIa and lactic acid or its ester 3(OSO 2R ') COOR 11, R '=Me, CF 3, 4-MeC 6H 4Deng] under alkaline condition, react, obtain target compound IId or, obtain the salt IIId of target compound, wherein R according to the salifying method of claim 3 11Be 1～4 carbon straight chain and branched hydrocarbyl.The used alkali of this reaction is NaHCO 3, KHCO 3, Na 2CO 3, K 2CO 3, Et 3N, ( I-Pr) 2NEt or pyridine, solvent for use are methylene dichloride, ethylene dichloride, chloroform, hexanaphthene, normal hexane, THF, DME, N, dinethylformamide or ethyl acetate.
Figure G2009102487285D00061
The preparation method of formula V type compound of the present invention such as Scheme 4: formula IVa compound or its salt is with aldehyde compound, in acidic conditions reaction down, form the target product V of similar ethylidene ether structure, or in organic solvents such as methyl alcohol, ethanol, THF, DME or ethyl acetate with sour salify, obtain salt formula target compound V.The acid of this reaction can be methylsulfonic acid, trifluoromethanesulfonic acid, trifluoroacetic acid or tosic acid etc.Work as R 10During=H, reaction can be adopted Paraformaldehyde 96 or formaldehyde solution; Work as R 10=CH 3The time, reaction can be adopted acetaldehyde, paraldehyde or acetaldehyde solution.
Figure G2009102487285D00071
Institute of the present invention synthetic part target compound is as table Table 1..
Table 1. institute of the present invention synthetic part target compounds
Figure G2009102487285D00072
Figure G2009102487285D00081
Figure G2009102487285D00111
Figure G2009102487285D00121
Figure G2009102487285D00131
Figure G2009102487285D00141
Figure G2009102487285D00151
Figure G2009102487285D00171
Figure G2009102487285D00181
Preferred compound of the present invention comprises 6,20,21,22,24,26,28,29,30,39,40,41,42,45,47,48,52,53,56,59,64,80,85,86,87,90,91.
The present invention has synthesized a series of novel tetrahydroisoquinolicompounds compounds (I, II, III, IV and V), and its preparation method is simple, favorable reproducibility.And has the anti-tumor activity of not seeing bibliographical information preferably.
Embodiment
Embodiment 1:6, the preparation of 7-dimethoxy-3-(5,6,7,8-tetrahydrochysene-1 ', 3 '-dioxole [4 ', 5 '-g]-5-isoquinolyl)-1 (3H)-isobenzofuran keto hydrochloride (1)
(1) N-(4, the 5-methylene-dioxy) styroyl-4, the preparation of 5-dimethoxy-3-oxo-isobenzofuran-1-acid amides (104)
Argon shield is also stirred down; the mixed liquid of homopiperony lamine 1.65g (10.0mmol) and methylene dichloride 20.0mL is slowly splashed into 4, in the mixed liquid of 5-dimethoxy-3-oxo isobenzofuran-1-carboxylic acid 2.38g (10.0mmol), DCC 2.17g (10.5mmol), DMAP0.12g (1.0mmol) and methylene dichloride 40.0mL.Drip and finish room temperature reaction 12.0h.The filtering insolubles adds water 50mL in reaction solution, divide and get organic layer, and water layer is with dichloromethane extraction (30mL * 2).Merge organic layer, successively with 1.0mol/L hydrochloric acid (50mL * 1), 1.0mol/L sodium hydrogen carbonate solution (50mL * 1) and saturated aqueous common salt (50mL * 1) washing, anhydrous sodium sulfate drying.Filter concentrating under reduced pressure, silica gel column chromatography (moving phase: PE: EA=3: 1) separate, get white solid 2.36g, yield 61.4%.
The preparation of (2) 6,7-dimethoxy-3-(5,6,7,8-tetrahydrochysene-1 ', 3 '-dioxole [4 ', 5 '-g]-5-isoquinolyl)-1 (3H)-isobenzofuran keto hydrochloride (1)
Argon shield is also stirred down, with the mixed liquid of compound 1040.77g (2.0mmol) and phosphorus oxychloride 5.0mL (10.0mmol) in 100 ℃ of heating 1.5h.Remove under reduced pressure after the excessive phosphorus oxychloride, in resistates, add methyl alcohol 20.0mL and destroy residual phosphorus oxychloride, be evaporated to dried.Residue is with methyl alcohol 8.0mL heating for dissolving, and solid is separated out in cooling.Suction filtration, the dry faint yellow solid that gets.
At ice bath and under stirring, above-mentioned faint yellow solid is dissolved in methyl alcohol 10.0mL, add sodium borohydride 0.23g (6mmol) then in batches.Finish, slowly rise to room temperature and continue reaction 12.0h.Transfer pH=1 with 1.0mol/L hydrochloric acid, be evaporated to dried.Add water 10.0mL dispersing and dissolving, remove organic impurity with ethyl acetate (5mL * 2) extraction.Water layer is transferred pH=9, extracts with ethyl acetate (10mL * 2).Merge organic layer, with saturated aqueous common salt (10mL * 2) washing, anhydrous sodium sulfate drying.Filter, concentrate residue.With the ethyl acetate solution 3.0mL salify of this resistates with 1.0mol/L hydrogenchloride, put coldly, separate out light yellow consubstantiality.With ethyl alcohol recrystallization, get white consubstantiality 0.51g, yield 60.8%.
MS(m/z)：370.1[M+H] +. 1H?NMR(d 6-DMSO)δ2.80～2.90(m，2H)，2.91～3.27(m，2H)，3.89(s，3H)，3.92(s，3H)，5.21(s，1H)，6.04(d，2H，J＝3.0)，6.27(s，1H)，6.85(s，1H)，7.19(s，1H)，7.40(d，1H，J＝8.4)，7.58(d，1H，J＝8.4)，8.51(s，1H)，9.21(s，1H)。
Embodiment 2:5, the preparation of 6-dimethoxy-3-(5,6,7,8-tetrahydrochysene-1 ', 3 '-dioxole [4 ', 5 '-g]-5-isoquinolyl)-1 (3H)-isobenzofuran keto hydrochloride (2)
The preparation method is with the preparation of compound 1, yield 57.6%.
MS(m/z)：370.1[M+H] +. 1H?NMR(D 2O)δ2.98～3.02(m，2H)，3.43～3.47(m，2H)，3.88(s，3H)，3.94(s，3H)，5.35(d，1H，J＝2.4)，5.96(d，2H，J＝10.9)，6.21(d，1H，J＝2.4)，6.29(s，1H)，6.68(s，1H)，6.85(s，1H)，7.37(s，1H)。
Embodiment 3:6, the preparation of 7-dimethoxy-3-(6,7-dimethoxy-1,2,3,4-tetrahydrochysene-1-isoquinolyl)-1 (3H)-isobenzofuran keto hydrochloride (3)
The preparation method is with the preparation of compound 1, yield 49.8%.
MS(m/z)：386.2[M+H] +. 1H?NMR(D 2O)δ3.00(d，2H，J＝6.0)，3.28(s，3H)，3.45～3.47(m，1H)，3.65～3.68(m，1H)，3.73(s，3H)，3.74(s，3H)，3.89(s，3H)，5.15(s，1H)，5.72(s，1H)，6.17(s，1H)，6.84(s，1H)，7.28(d，1H，J＝8.4)，7.54(d，1H，J＝8.4)。
Embodiment 4:5, the preparation of 6-dimethoxy-3-(6,7-dimethoxy-1,2,3,4-tetrahydrochysene-1-isoquinolyl)-1 (3H)-isobenzofuran keto hydrochloride (4)
The preparation method is with the preparation of compound 1, yield 55.6%.
MS(m/z)：386.2[M+H] +. 1H?NMR(D 2O)δ2.85～2.96(m，2H)，3.32～3.49(m，5H)，3.34(s，1H)，3.71(s，3H)，3.80(s，3H)，3.84(s，3H)，5.18(s，1H)，6.14(s，1H)，6.16(s，1H)，6.73(s，1H)，6.83(s，1H)，7.23(d，1H，J＝4.8)。
The preparation of embodiment 5:6-methoxyl group-3-(5,6,7,8-tetrahydrochysene-1 ', 3 '-dioxole [4 ', 5 '-g]-5-isoquinolyl)-1 (3H)-isobenzofuran keto hydrochloride (5)
The preparation method is with (1), yield 46.7%.
MS(m/z)：354.2[M+H] +. 1H?NMR(D 2O)δ2.83～2.86(m，2H)，3.30～3.22(m，2H)，3.77(s，3H)，5.20(d，1H，J＝1.8)，5.79(s，1H)，5.83(s，1H)，6.16(d，1H，J＝4.2)，6.17(s，1H)，6.68(s，1H)，7.01(d，1H，J＝9.0)，7.28(d，1H，J＝2.4)。
Embodiment 6:4, the preparation of 6-dimethoxy-3-(5,6,7,8-tetrahydrochysene-1 ', 3 '-dioxole [4 ', 5 '-g]-5-isoquinolyl)-1 (3H)-isobenzofuran keto hydrochloride (6)
The preparation method is with the preparation of compound 1, yield 59.7%.
MS(m/z)：370.1[M+H] +. 1H?NMR(d 6-DMSO).δ2.93(t，2H，J＝6.0)，2.46(d，2H，J＝6.0)，3.85(s，3H)，3.96(s，3H)，5.05(s，1H)，5.58(s，1H)，5.86(s，1H)，5.92(s，1H)，6.17(s，1H)，6.81(s，1H)，6.87(d，1H，J＝1.8)，7.05(d，1H，J＝2.4)。
Embodiment 7:4, the preparation of 6-dimethoxy-3-(6,7-dimethoxy-1,2,3,4-tetrahydrochysene-1-isoquinolyl)-1 (3H)-isobenzofuran keto hydrochloride (7)
The preparation method is with the preparation of compound 1, yield 63.2%.
MS(m/z)：386.2[M+H] +. 1H?NMR(D2O)δ3.03～3.06(m，2H)，3.22(s，3H)，3.54(m，1H)，3.73(s，1H)，3.79～3.84(m，4H)，3.98(s，1H)，5.28(s，1H)，5.53(s，1H)，6.15(s，1H)，6.83(s，2H)，7.04(d，1H，J＝1.2)
Embodiment 8:6, the preparation of 7-dimethoxy-3-(5,6,7-trimethoxy-1,2,3,4-tetrahydrochysene-1-isoquinolyl)-1 (3H)-isobenzofuran keto hydrochloride (8)
The preparation method is with the preparation of compound 1, yield 40.3%
MS(m/z)：416.1[M+H] +. 1H?NMR(D2O)δ3.02～3.06(m，2H)，3.39(s，3H)，3.59(m，1H)，3.65～3.83(m，7H)，3.88(s，3H)，3.98(s，3H)，5.25(s，1H)，5.70(s，1H)，6.27(s，H)，7.41(d，1H，J＝11.4)，7.65(d，1H，J＝11.4)。
Embodiment 9:(R)-6,7-dimethoxy-3-((1S, 3S)-6,7-dimethoxy-3-methyl isophthalic acid, 2,3,4-tetrahydrochysene-1-isoquinolyl)-1 (3H)-isobenzofuran keto hydrochloride (9) and (S)-6,7-dimethoxy-3-((1R, 3S)-6,7-dimethoxy-3-methyl isophthalic acid, 2,3,4-tetrahydrochysene-1-isoquinolyl) preparation of-1 (3H)-isobenzofuran keto hydrochloride (10)
The preparation method is with the preparation of compound 1, obtains the free alkali of compound through column chromatography for separation, under ice bath, respectively with the ethyl acetate solution salify of hydrogenchloride, compound 9 and compound 10, total recovery 81.3%.
Compound 9:MS (m/z): 400.2[M+H] +. 1H NMR (D 2O) δ 1.29 (d, 3H, J=6.3), 2.84～2.88 (m, 2H), 3.52 (m, 1H), 3.74 (s, 3H), 3.78 (s, 3H), 3.87 (s, 3H), 3.89 (s, 3H), 5.29 (s, 1H), 6.33 (s, H), 6.84 (s, 1H), 7.01 (s, 1H) 7.34 (d, 1H, and J=8.4) 7.48 (d, 1H, J=8.4).
Compound 10:MS (m/z): 400.2[M+H] +. 1H NMR (D 2O) δ 1.40 (d, 3H, J=6.3), 2.70 (m, 1H), 3.09 (s, 1H), 3.19 (s, 3H), 3.68 (s, 3H), 3.70 (s, 3H), 3.86 (s, 3H), 4.04 (s, 1H), 5.09 (s, H), 5.49 (s, 1H), 6.10 (s, 1H), 6.78 (s, 1H), 7.40 (d, 1H, J=8.4), 7.55 (d, 1H, J=8.4).
Embodiment 10:4,5, the preparation of 6-trimethoxy-3-(5,6,7,8-tetrahydrochysene-1 ', 3 '-dioxole [4 ', 5 '-g]-5-isoquinolyl)-1 (3H)-isobenzofuran keto hydrochloride (11)
The preparation method is with the preparation of compound 1, yield 65.2%.
MS(m/z)：384.1[M+H] +. 1H?NMR(d 6-DMSO)δ2.96(d，2H，J＝6.0)，3.46(d，2H，J＝6.3)，3.90(m，9H)，5.02(s，1H)，5.64(s，1H)，5.91(d，2H)，6.33(s，1H)，6.82(s，1H)，7.17(s，1H)，9.91(s，2H)。
Embodiment 11:6, the preparation of 7-dimethoxy-3-(4-methoxyl group-9-bromo-5,6,7,8-tetrahydrochysene-1 ', 3 '-dioxole [4 ', 5 '-g]-5-isoquinolyl)-1 (3H)-isobenzofuran keto hydrochloride (12)
The preparation method is with the preparation of compound 1, yield 57.6%.
MS(m/z)：478.0[M+H] +。 1H?NMR(d 6-DMSO)δ.2.73～2.78(m，2H)，3.02(m，2H)，3.50(s，3H)，3.85(s，3H)，3.86(s，3H)，5.30(s，1H)，6.02(s，1H)，6.11(d，2H，J＝6.7)，7.03(d，1H，J＝8.9)，7.52(d，1H，J＝8.5)
Embodiment 12:6, the preparation of 7-dimethoxy-3-(5,6,7,8-tetrahydrochysene-6-methyl isophthalic acid ', 3 '-dioxole [4 ', 5 '-g]-5-isoquinolyl)-1 (3H)-isobenzofuranone (13)
Under agitation, compound 10.41g (1.0mmol) is added in the mixed liquid of 37% formalin 0.50mL (7.0mmol) and 88% formic acid 0.5mL (12.0mmol), be warming up to 100 ℃ gradually, reaction 8h.Be cooled to room temperature, add the hydrochloric acid 2.0mL of 6.0mol/L, continue to stir 2h.Be evaporated to driedly, add water 10.0mL in the residue, transfer pH=9, extract with ethyl acetate (10.0mL * 2).Merge organic layer, with saturated aqueous common salt (10mL * 2) washing, anhydrous sodium sulfate drying.Filter, concentrate, the gained crude product is after column chromatography for separation, and pure product get white solid 0.32g, yield 75.3% with the ethyl acetate solution 2.0mL salify of 1.0mol/L hydrogenchloride.
MS(m/z)：384.2[M+H] +. 1H?NMR(CDCl 3)δ2.05～2.32(m，1H)，2.55(s，3H)，2.57～2.66(m，2H)，2.88(m，1H)，3.88(s，3H)，3.99(d，1H，J＝3.9)，4.06(s，3H)，5.49(d，1H，J＝3.9)，5.91(s，2H)，6.38(s，1H)，6.51(d，1H，J＝8.2)，6.58(s，1H)，7.07(d，1H，J＝8.2)。
Embodiment 13:5, the preparation of 6-dimethoxy-3-(5,6,7,8-tetrahydrochysene-6-methyl isophthalic acid ', 3 '-dioxole [4 ', 5 '-g]-5-isoquinolyl)-1 (3H)-isobenzofuran keto hydrochloride (14)
The preparation method is with the preparation of compound 13, yield 70.2%.
MS(m/z)：384.2[M+H] +. 1H?NMR(D 2O)δ2.98～3.07(m，5H)，3.39(s，1H)，3.70(m，2H)，3.83(s，3H)，3.91(s，3H)，5.01(s，1H)，5.69(s，1H)，5.75(s，1H)，5.81(s，1H)，6.12(s，1H)，6.73(s，1H)，7.07(s，1H)，7.21(s，1H)。
Embodiment 14:6, the preparation of 7-dimethoxy-3-(2-methyl-6,7-dimethoxy-1,2,3,4-tetrahydrochysene-1-isoquinolyl)-1 (3H)-isobenzofuranone (15)
The preparation method is with the preparation of compound 13, yield 52.8%.
MS(m/z)：400.2[M+H] +. 1HNMR(CDCl 3)δ2.44(d，1H)，2.53～2.57(m，1H)，2.65(s，3H)，2.71～2.76(m，1H)，3.05～3.09(m，1H)，3.74(s，3H)，3.83(d，6H)，3.91(s，3H)，4.06(d，1H，J＝1.5)，5.60(d，1H，J＝1.5)，6.35(s，1H)，6.68(s，1H)，7.00(d，1H，J＝8.4)，7.30(d，1H，，J＝8.4)。
Embodiment 15:5, the preparation of 6-dimethoxy-3-(2-methyl-6,7-dimethoxy-1,2,3,4-tetrahydrochysene-1-isoquinolyl)-1 (3H)-isobenzofuranone (16)
The preparation method is with the preparation of compound 13, yield 62.3%.
MS(m/z)：400.2[M+H] +. 1H?NMR(CDCl 3)δ2.35(m，1H?2.57～2.64(m，5H)，2.91～2.94(s，1H)，2.93(m，1H)，3.74(s，3H)，3.77(s，3H)，3.86(s，3H)，3.91(s，3H)，4.09(d，1H，J＝8.4)，5.56(d，1H，J＝8.4)，6.17(s，1H)，6.45(s，1H)，6.61(s，1H)，7.25(s，1H)。
The preparation of embodiment 16:6-methoxyl group-3-(5,6,7,8-tetrahydrochysene-6-methyl isophthalic acid ', 3 '-dioxole [4 ', 5 '-g]-5-isoquinolyl)-1 (3H)-isobenzofuranone (17)
The preparation method is with the preparation of compound 13, yield 49.8%.
MS(m/z)：366.8[M+H] +. 1H?NMR(CDCl 3)δ2.23(m，1H)，2.45～2.59(m，5H)，2.45(m，1H)，3.85(s，3H)，4.02(d，1H，J＝3.6)，5.54(d，1H，J＝3.6)，5.94(s，2H)，6.50(s，1H)，6.59(s，1H)，6.70(d，1H，J＝8.4)，7.29(s，1H)。
Embodiment 17:(R)-6,7-dimethoxy-3-(preparation of (1S, 3S)-6,7-dimethoxy-2,3-dimethyl-1,2,3,4-tetrahydrochysene-1-isoquinolyl)-1 (3H)-isobenzofuranone (18)
The preparation method is with the preparation of compound 13, yield 49.8%, yield 57.4%.
MS(m/z)：414.2[M+H] +. 1H?NMR(CDCl 3)δ1.27(d，3H，J＝5.4)，2.31(m，3H)，2.57(s，3H)，3.73(s，3H)，3.82(s，3H)，3.82(s，3H)，3.88(s，3H)，4.10(s，1H，J＝3.4)，5.52(s，1H，J＝3.5)，6.31(s，1H)，6.72(s，1H，)，7.01(d，1H，J＝8.1)7.34(d，1H，J＝8.1)。
Embodiment 18:(S)-6,7-dimethoxy-3-(preparation of (1R, 3S)-6,7-dimethoxy-2,3-dimethyl-1,2,3,4-tetrahydrochysene-1-isoquinolyl)-1 (3H)-isobenzofuran keto hydrochloride (19)
The preparation method is with the preparation of compound 13, yield 52.1%.
MS(m/z)：414.2[M+H] +. 1H?NMR(D 2O)δ1.52(d，3H，J＝6.3)，2.72～2.96(m，2H)，3.19(d，6H)，3.56(s，3H)，3.68(s，3H)，3.80～3.85(m，4H)，4.99(s，1H)，5.56(s，1H)，6.21(s，1H)，6.76(s，H)，7.51(d，1H，J＝8.4)，7.55(d，1H，J＝8.4)。
Embodiment 19:6, the preparation of 7-dimethoxy-3-(4-methoxyl group-6-methyl-9-bromo-5,6,7,8-tetrahydrochysene-1 ', 3 '-dioxole [4 ', 5 '-g]-5-isoquinolyl)-1 (3H)-isobenzofuran keto hydrochloride (20)
The preparation method is with the preparation of compound 13, yield 61.4%.
MS(m/z)：494.1[M+H] +. 1H?NMR(d 6-DMSO)δ2.73(s，3H)，2.81～2.90(m，2H)，3.27(s，3H)，3.42～3.50(m，2H)，3.81(s，3H)，3.88(s，3H)，5.31(s，1H)，6.07(s，2H)，6.18(s，1H)，7.44(d，1H，J＝7.1)，7.60(d，1H，J＝7.1)，11.59(s，1H)。
Embodiment 20:5-(2, the 3-veratryl)-5,6,7,8-tetrahydrochysene-1 ', the preparation of 3 '-dioxole [4 ', 5 '-g]-5-isoquinoline hydrochloride (21)
(1) preparation of N-(2-(4, the 5-methylenedioxyphenyl) ethyl)-2-(2, the 3-Dimethoxyphenyl) ethanamide (105)
Under argon shield and stirring, with the mixed liquid heating reflux reaction 4.0h of homopiperony lamine 1.96g (0.01mol) with thionyl chloride 5.0mL.Concentrating under reduced pressure, residue dissolves with ether 20.0mL.Ice bath also stirs down, and this diethyl ether solution is slowly dripped to the mixed liquid of compound 11.65g (0.01mol), ether 20.0mL and 6.0% sodium carbonate solution 20.0mL, separates out white solid gradually.Drip and finish, continue to stir 1.0h.Suction filtration, drying gets solid 2.7g, yield 78.0%.
(2) 5-(2, the 3-veratryl)-5,6,7,8-tetrahydrochysene-1 ', the preparation of 3 '-dioxole [4 ', 5 '-g]-5-isoquinoline hydrochloride (21)
Argon shield is also stirred down, with compound 105 0.68g (2.0mmol) 100 ℃ of reacting by heating 1.5h of mixed liquid with phosphorus oxychloride 5.0mL (10.0mmol).Remove under reduced pressure after the excessive phosphorus oxychloride, in resistates, add methyl alcohol 20.0mL and destroy residual phosphorus oxychloride, be evaporated to dried.Residue is with methyl alcohol 8.0mL heating for dissolving, and solid is separated out in cooling.Suction filtration, the dry faint yellow solid that gets.
At ice bath and under stirring, above-mentioned faint yellow solid is dissolved in methyl alcohol 20mL, add sodium borohydride 0.23g (6mmol) then in batches.Finish, slowly rise to room temperature and continue reaction 12.0h.Transfer pH=1.0 with 1.0mol/L hydrochloric acid, be evaporated to dried.Add water 10.0mL dispersing and dissolving, remove organic impurity with ethyl acetate (5mL * 2) extraction.Water layer is transferred pH=9, with ethyl acetate (10mL * 2) extraction, anhydrous sodium sulfate drying.Filter, concentrate residue.With the acetic acid ethyl fluid 3.0mL of 1.0mol/L HCl heating dispersing and dissolving, put coldly this resistates, separate out light yellow solid.With ethyl alcohol recrystallization, get white solid 0.60g, yield 80.7%.
MS(m/z)：328.1[M+H] +. 1H?NMR(d 6-DMSO)δ2.98～3.05(m，2H)，3.11～3.15(m，1H)，3.34～3.38(m，1H)，3.40～3.43(m，1H)，3.56～3.59(s，1H)，3.72(s，3H)，3.86(s，3H)，4.68(t，1H，J＝3.6)，5.91(d，2H，J＝6.8)，6.52(s，1H)，6.73(s，1H)，6.88(d，1H，J＝7.8)，7.07(d，1H，J＝7.8)，7.07(t，1H，J＝7.8)。
Embodiment 21:1-(2, the 3-dimethoxy-benzyl)-5,6-dimethoxy-1,2,3, the preparation preparation method of 4-four hydrogen isoquinoline hydrochloric acid salt (22) is with the preparation of compound 21, yield 78.5%.
MS(m/z)：344.2[M+H] +. 1H?NMR(D 2O)δ2.91～2.93(m，2H)，3.04～3.08(m，1H)，3.22～3.25(m，1H)，3.32～3.34(m，1H)，3.38(s，3H)，3.44(s，3H)，3.52～3.54(m，1H)，3.65(s，3H)，3.72(s，3H)，4.60(t，1H，J＝7.8)，6.05(s，1H)，6.73(s，1H)，6.75(d，1H，J＝7.8)，6.94(d，1H，J＝8.4)，7.02(t，1H，J＝7.8)。
Embodiment 22:1-(2, the 3-dimethoxy-benzyl)-6,7-dimethoxy-1,2,3, the preparation of 4-four hydrogen isoquinoline hydrochloric acid salt (23)
The preparation method is with the preparation of compound 21, yield 83.2%.
MS(m/z)：344.2[M+H] +.1H?NMR(D 2O)δ2.91～2.93(m，2H)，3.04～3.08(m，1H)，3.22～3.25(m，1H)，3.32～3.34(m，1H)，3.39(s，3H)，3.44(s，3H)，3.51～3.54(m，1H)，3.65(s，3H)，3.72(s，3H)，4.60(t，1H，J＝7.8)，6.05(s，1H)，6.73(s，1H)，6.75(d，1H，J＝7.8)，6.94(d，1H，J＝8.4)，7.02(t，1H，J＝7.2)。
Embodiment 23:5-(3, the 5-dimethoxy-benzyl)-5,6,7,8-tetrahydrochysene-1 ', the preparation of 3 '-dioxole [4 ', 5 '-g]-5-isoquinoline hydrochloride (24)
The preparation method is with the preparation of compound 21, yield 75.5%.
MS(m/z)：328.1[M+H] +. 1H?NMR(d 6-DMSO)δ2.81～2.87(m，1H)，2.96～3.04(m，2H)，3.12～3.15(m，1H)，3.28～3.32(m，2H)，3.73(s，6H)，4.63(s，1H)，5.99(d，2H，J＝3.6)，6.42(s，1H)，6.58(s，2H)，6.80(s，1H)，6.86(s，1H)，9.04(s，1H)，9.13(s，1H)。
Embodiment 24:1-(benzo [d] 1 ', 3 '-dioxole-5-yl) methyl-6,7-dimethoxy-1,2,3, the preparation of 4-four hydrogen isoquinoline hydrochloric acid salt (25)
The preparation method is with the preparation of compound 21, yield 86.8%.
MS(m/z)：328.1[M+H] +. 1H?NMR(d 6-DMSO)δ2.81～2.87(m，1H)，2.96～3.04(m，2H)，3.12～3.15(m，1H)，3.28～3.32(m，2H)，3.73(s，6H)，4.63(s，1H)，5.99(d，2H，J＝3.6)，6.42(s，1H)，6.58(s，2H)，6.80(s，1H)，6.86(s，1H)，9.04(s，1H)，9.13(s，1H)。
Embodiment 25:1-(benzo [d] 1 ', 3 '-dioxole-5-yl) methyl-6,8-dimethoxy-1,2,3, the preparation of 4-four hydrogen isoquinoline hydrochloric acid salt (26)
The preparation method is with the preparation of compound 21, yield 82.6%.
MS(m/z)：328.1[M+H] +. 1H?NMR(d6-DMSO)δ2.49～3.03(m，3H)，3.06～3.13(m，1H)，3.16～3.18(m，1H)，3.75(s，3H)，3.77(s，3H)，4.58(s，1H)，6.00(s，2H)，6.41(d，1H，J＝1.8)，6.48(d，1H，J＝2.4)，6.74～6.75(m，1H)，6.86～6.89(m，2H)，8.70(s，1H)，9.60(s，1H)。
Embodiment 26:1-(benzo [d] 1 ', 3 '-dioxole-5-yl) methyl-5,6-dimethoxy-1,2,3, the preparation of 4-four hydrogen isoquinoline hydrochloric acid salt (27)
The preparation method is with the preparation of compound 21, yield 84.1%.
MS(m/z)：328.1[M+H] +. 1HNMR(d 6-DMSO)δ2.92～3.38(m，6H)，3.72(s，3H)，3.79(s，3H)，4.63(s，1H)，6.01(s，2H)，6.80(d，1H，J＝8.1)，6.90(d，1H，J＝8.1)，6.93～7.00(m，3H)，9.09(s，1H)。
Embodiment 27:5-(3-bromo-4-methoxy-benzyl)-5,6,7,8-tetrahydrochysene-1 ', the preparation of 3 '-dioxole [4 ', 5 '-g]-5-isoquinoline hydrochloride (28)
The preparation method is with the preparation of compound 21, yield 85.6%.
MS(m/z)：376.0[M+H] +. 1H?NMR(d 6-DMSO)δ2.81～3.35(m，6H)，4.59(s，1H)，5.98(m，2H，J＝3.9)，6.79(s，1H)，6.86(s，1H)，7.10(d，1H，J＝8.4)，7.37(d，1H，J＝8.4)，7.66(d，1H，J＝1.8)，9.22(s，2H)。
Embodiment 28:1-(3-bromo-4-methoxy-benzyl) methyl-6,8-dimethoxy-1,2,3, the preparation of 4-four hydrogen isoquinoline hydrochloric acid salt (29)
The preparation method is with the preparation of compound 21, yield 83.3%
MS(m/z)：392.1[M+H] +. 1H?NMR(d 6-DMSO)δ2.94～3.37(m，6H)，3.72(s，3H)，3.75(s，3H)，3.83(s，3H)，4.62(s，1H)，6.42(s，1H)，6.47(s，1H)，7.08(d，1H，J＝8.4)，7.24(d，1H，J＝8.4)，7.75(s，1H)，8.69(s，1H)，9.44(s，1H)。
Embodiment 29:(3S)-and 1-(3-bromo-4-methoxy-benzyl) methyl-3-methyl-6,7-dimethoxy-1,2,3, the preparation of 4-four hydrogen isoquinoline hydrochloric acid salt (30)
The preparation method is with the preparation of compound 21, yield 78.5%.
MS(m/z)：406.2[M+H] +. 1H?NMR(D 2O)δ1.34(d，3H，J＝6.3)，2.75～3.00(m，3H)，3.24～3.44(m，2H)，3.57(s，3H)，3.72(s，3H)，3.78(s，3H)，4.62(t，1H，J＝6.6)，6.57(s，1H)，6.75(s，1H)，6.98(d，1H，J＝8.7)，7.23(d，1H，J＝8.7)，7.40(s，1H)
Embodiment 30:(3S)-and 1-(benzo [d] 1 ', 3 '-dioxole-5-yl) methyl-3-methyl-6,7-dimethoxy-1,2,3, the preparation of 4-four hydrogen isoquinoline hydrochloric acid salt (31)
The preparation method is with the preparation of compound 21, yield 84.7%.
MS(m/z)：342.2[M+H] +. 1H?NMR(D 2O)δ1.32(d，3H，J＝6.6)，2.77～2.97(m，3H)，3.35～3.46(m，2H)，3.67(s，3H)，3.74(s，3H)，4.64(s，1H)，5.89(s，2H)，6.74～6.84(s，5H)。
Embodiment 31:(3S)-and 1-(2, the 3-dimethoxy-benzyl) methyl-3-methyl-6,7-dimethoxy-1,2,3, the preparation of 4-four hydrogen isoquinoline hydrochloric acid salt (32)
The preparation method is with the preparation of compound 21, yield 82.5%.
MS(m/z)：358.2[M+H] +. 1H?NMR(D 2O)δ1.35(d，3H，J＝6.3)，2.78～2.82(m，2H)，3.01～3.08(m，1H)，3.33～3.47(m，3H)，3.57(s，3H)，3.70(s，6H)，3.80(s，3H)，6.53(s，1H)，6.72(s，1H)，6.81(d，1H，J＝7.2)，6.99(d，1H，J＝7.2)，7.07(t，1H，J＝8.1)
Embodiment 32:(3R)-and 1-(benzo [d] 1 ', 3 '-dioxole-5-yl) methyl-3-methyl-7-methoxyl group-1,2,3, the preparation of 4-four hydrogen isoquinoline hydrochloric acid salt (33)
The preparation method is with the preparation of compound 21, yield 28%.
MS(m/z)：342.2[M+H] +. 1H?NMR(D 2O)δ1.32(s，3H)，2.77～2.97(m，2H)，3.35～3.46(m，2H)，3.74(s，3H)，4.64(s，1H)，5.89(s，2H)，6.74～6.84(s，6H)
Embodiment 33:(3R)-and 1-(4-methoxy-benzyl)-3-methyl-7-methoxyl group-1,2,3, the preparation of 4-four hydrogen isoquinoline hydrochloric acid salt (34)
The preparation method is with the preparation of compound 21, yield 26%.
MS(m/z)：342.2[M+H] +. 1H?NMR(D 2O)δ1.32(s，3H)，2.77～2.97(m，2H)，3.23(s，1H)，3.35～3.46(m，2H)，3.74(s，3H)，3.78(s，3H)，4.64(s，1H)，6.74～6.84(m，7H)。
Embodiment 34:(3R)-and 1-(3-bromo-4-methoxy-benzyl) methyl-3-methyl-6,7-dimethoxy-1,2,3, the preparation of 4-four hydrogen isoquinoline hydrochloric acid salt (35)
The preparation method is with the preparation of compound 21, yield 78.5%.
MS(m/z)：406.2[M+H] +. 1H?NMR(D 2O)δ1.34(d，3H，J＝6.3)，2.75～3.00(m，3H)，3.24～3.44(m，2H)，3.57(s，3H)，3.72(s，3H)，3.78(s，3H)，4.62(t，1H，J＝6.6)，6.57(s，1H)，6.75(s，1H)，6.98(d，1H，J＝8.7)，7.23(d，1H，J＝8.7)，7.40(s，1H)。
Embodiment 35:(3R)-and 1-(benzo [d] 1 ', 3 '-dioxole-5-yl) methyl-3-methyl-6,7-dimethoxy-1,2,3, the preparation of 4-four hydrogen isoquinoline hydrochloric acid salt (36)
The preparation method is with the preparation of compound 21, yield 84.7%.
MS(m/z)：342.2[M+H] +. 1H?NMR(D 2O)δ1.32(d，3H，J＝6.6)，2.77～2.97(m，3H)，3.35～3.46(m，2H)，3.67(s，3H)，3.74(s，3H)，4.64(s，1H)，5.89(s，2H)，6.74～6.84(s，5H)。
Embodiment 36:(3R)-and 1-(2, the 3-dimethoxy-benzyl) methyl-3-methyl-6,7-dimethoxy-1,2,3, the preparation of 4-four hydrogen isoquinoline hydrochloric acid salt (37)
The preparation method is with the preparation of compound 21, yield 82.5%.
MS(m/z)：358.2[M+H] +. 1H?NMR(D 2O)δ1.35(d，3H，J＝6.3)，2.78～2.82(m，2H)，3.01～3.08(m，1H)，3.33～3.47(m，3H)，3.57(s，3H)，3.70(s，6H)，3.80(s，3H)，4.72(t，1H，J＝6.6)，6.53(s，1H)，6.72(s，1H)，6.81(d，1H，J＝7.2)，6.99(d，1H，J＝7.2)，7.07(t，1，J＝8.1)。
Embodiment 37:(3R)-and 1-(3, the 4-Dimethoxyphenyl) methyl-3-methyl-6,7-dimethoxy-1,2,3, the preparation of 4-four hydrogen isoquinoline hydrochloric acid salt (38)
The preparation method is with the preparation of compound 21, yield 84.7%.
MS(m/z)：342.2[M+H] +. 1H?NMR(D 2O)δ1.34(s，3H)，2.77～2.97(m，2H)，3.23(s，1H)，3.35～3.46(m，2H)，3.74(s，3H)，3.76(s，3H)，3.87(s，6H)，4.64(s，1H)，6.74～6.84(m，5H)。
Embodiment 38:(R)-5-(4-methoxy-benzyl)-5,6,7,8-tetrahydrochysene-1 ', 3 '-dioxole [4 ', 5 '-g] isoquinoline hydrochloride (39) and (S)-5-(4-methoxy-benzyl)-5,6,7,8-tetrahydrochysene-1 ', 3 '-dioxole [4 ', 5 '-g] preparation of isoquinoline hydrochloride (40)
The preparation method is with the preparation of compound 21, obtains the free alkali of compound through column chromatography for separation, under ice bath, gets compound 39 and compound 40, total recovery 78.0% with hydrogenchloride ethyl acetate solution salify respectively.
Compound 39 and compound 40:MS (m/z): 300.1[M+H] +. 1H NMR (DMSO-d 6), δ 2.83～2.96 (m, 2H), 3.00～3.12 (m, 1H), 3.18 (m, 1H), 3.26～3.28 (m, 1H), 3.30 (m, 1H), 3.75 (s, 3H), 4.58 (m, 1H), 5.99 (s, 2H), 6.73 (s, 1H), 6.80 (s, 1H), 6.93 (d, 2H, J=8.4), 7.28 (d, 2H, J=8.4), 9.12 (s, 2H).
Embodiment 39:(5R)-5-(benzo [d] 1 ', 3 '-dioxole-5-yl) methyl-5,6,7,8-tetrahydrochysene-1 ', 3 '-dioxole [4 ', 5 '-g] isoquinoline hydrochloride (41) and (5S)-5-(benzo [d] 1 ', 3 '-dioxole-5-yl) methyl-5,6,7,8-tetrahydrochysene-1 ', the preparation of 3 '-dioxole [4 ', 5 '-g] isoquinoline hydrochloride (42)
The preparation method is with the preparation of compound 21, obtains the free alkali of compound through column chromatography for separation, under ice bath, gets compound 41 and compound 42, total recovery 73% with hydrogenchloride ethyl acetate solution salify respectively.
Compound 41 and compound 42:MS (m/z): 354.1[M+H] + 1. 1H NMR (CDCl 3), δ 2.69～2.82 (m, 2H), 2.84～2.86 (m, 1H), 2.86～2.90 (m, 1H), 3.06～3.19 (m, 2H), 4.04 (t, 1H, J=6.3), 5.92 (d, 4H, J=12), 6.56 (s, 1H), 6.69 (d, 2H, J=6.6), 6.74～6.78 (m, 2H).
Embodiment 40:(5R)-5-(3, the 4-dimethoxy-benzyl)-5,6,7,8-tetrahydrochysene-1 ', 3 '-dioxole [4 ', 5 '-g] isoquinoline hydrochloride (43) and (5S)-5-(3, the 4-dimethoxy-benzyl)-5,6,7,8-tetrahydrochysene-1 ', the preparation of 3 '-dioxole [4 ', 5 '-g] isoquinoline hydrochloride (44)
The preparation method is with the preparation of compound 21, obtains the free alkali of compound through column chromatography for separation, under ice bath, gets compound 43 and compound 44, total recovery 71.0% with hydrogenchloride ethyl acetate solution salify respectively.
Compound 43 and compound 44:MS (m/z): 346.1[M+H] +. 1H NMR (DMSO-d 6), δ 2.82～3.15 (m, 4H), 3.28～3.45 (m, 2H), 3.74 (s, 6H), 4.60 (s, 1H), 6.00 (s, 2H), 6.81 (d, 2H, J=1.5), 6.88 (d, 1H, J=1.5), 6.92～6.95 (m, 1H), 9.20 (s, 2H).
Embodiment 41:5-(4-benzyloxy benzyl)-5,6,7,8-tetrahydrochysene-1 ', the preparation of 3 '-dioxole [4 ', 5 '-g] isoquinoline hydrochloride (45)
The preparation method is with the preparation of compound 21, yield 79.0%.
MS(m/z)：299.1[M+H] +. 1H?NMR(DMSO-d 6)δ1.95(s，1H)，2.46～2.75(m，2H)，2.84～3.05(m，?2H)，3.25～3.35(m，2H)，4.29(s，1H)，5.16(s，1H)，6.07(s，2H)，6，91(s，2H)，6.94(s，2H)，7.18(s，2H)，7.38～7.47(m，5H)，9.20(s，2H，NH，HCl)。
Embodiment 42:5-(4-hydroxybenzyl)-5,6,7,8-tetrahydrochysene-1 ', the preparation of 3 '-dioxole [4 ', 5 '-g] isoquinoline hydrochloride (46)
To the hydrogen of the mixed liquid incision 3atm of compound 452.0g (5.0mmol), 10% palladium charcoal 0.2g and ethanol 40.0mL, room temperature vigorous stirring catalytic hydrogenation 48h.Filtering palladium charcoal, concentrating under reduced pressure, resistates get white solid 1.08g, yield 68.0% through re-crystallizing in ethyl acetate.
MS(m/z)：299.1[M+H] +. 1H?NMR(DMSO-d 6)δ1.95(s，1H)，2.46～2.75(m，2H)，2.84～3.05(m，2H)，3.25～3.35(m，2H)，4.29(s，1H)，5.16(s，1H)，6.07(s，2H)，6.91(s，2H)，6.94(s，2H)，7.18(s，2H)，9.20(s，1H，HCl)。
Embodiment 43:1-(3,4-two inferior p-methoxy-phenyls) methyl-4-methoxyl group-9-bromo-5,6,7,8-tetrahydrochysene-1 ', the preparation of 3 '-dioxole [4,5-g]-5-isoquinoline hydrochloride (47)
The preparation method is with the preparation of compound 21, yield 67.9%.
MS(m/z)：400.1[M+H] +. 1H?NMR(d 6-DMSO)δ2.72～2.84(m，2H)，2.90～3.02(m，2H)，3.39～3.44(m，1H)，3.9(s，3H)，4.69(m，1H)，6.01(s，2H)，6.13(d，2H，J＝5.1)，6.75(d，1H，J＝7.9)，6.89～6.91(m，2H)，8.56(s，1H)，9.42(s，1H)。
Embodiment 44:1-(3-bromo-4-p-methoxy-phenyl) methyl-4-methoxyl group-9-bromo-5,6,7,8-tetrahydrochysene-1 ', the preparation of 3 '-dioxole [4,5-g]-5-isoquinoline hydrochloride (48)
The preparation method is with the preparation of compound 21, yield 61.3%.
MS(m/z)：466.1[M+H] +. 1H?NMR(d 6-DMSO)δ2.83(d，2H，J＝5.5)，3.04(d，2H，J＝5.5)，3.24～3.44(m，2H)，3.82(d，3H，J＝7.3)，3.89(s，3H)，4.74(t，1H)，6.12(d，2H，J＝7.1)，7.11(d，1H，J＝8.4)，7.27(d，1H，J＝8.4)，7.52(s，1H)，8.99(s，1H)。
Embodiment 45:1-(4, the 5-Dimethoxyphenyl) methyl-6-methyl-9-bromo-5,6,7,8-tetrahydrochysene-1 ', the preparation of 3 '-dioxole [4,5-g]-5-isoquinoline hydrochloride (49)
The preparation method is with the preparation of compound 21, yield 74.8%.
MS(m/z)：446.1[M+H] +. 1H?NMR(d 6-DMSO)δ2.83～2.90(m，1H)，2.94～3.02(m，2H)，3.14～3.24(m，1H)，3.33～3.43(m，1H)，3.74(s，3H)，3.84(s，3H)，4.65(s，1H)，6.01(d，2H)，6.82(s，1H)，6.96(s，1H)，7.19(s，1H)，7.24(s，1H)，9.02(s，1H)。
Embodiment 46:5-(2, the 3-dimethoxy-benzyl)-6-methyl-5,6,7,8-tetrahydrochysene-1 ', the preparation of 3 '-dioxole [4 ', 5 '-g]-5-isoquinoline hydrochloride (50)
Under agitation, the mixed liquid chamber temperature reaction 5.0h with compound 210.18g (0.5mmol), 37% formaldehyde solution 0.5mL (7.0mmol) and methyl alcohol 2.0mL through the ice bath cooling, adds sodium borohydride 0.23g (6.0mmol) more in batches in this mixed liquid.Finish, continue stirring reaction 8.0h.Add water 10.0mL,, merge organic phase, anhydrous sodium sulfate drying with ethyl acetate (10mL * 2) extraction.Filter, concentrate, the gained crude product separates through silica gel column chromatography, oily matter again under ice bath the acetic acid ethyl fluid with hydrogenchloride handle salify, hydrochloride 0.14g, yield 80.5%.
MS(m/z)：342.2[M+H] +. 1H?NMR(D 2O)δ2.82(s，2H)，3.04(s，3H)，3.18～3.20(m，2H)，3.25～3.32(m，1H)，3.55(s，3H)，3.78(s，4H)，4.50(t，1H，J＝7.5)，5.81(s，2H)，6.02(s，1H)，6.70～6.77(m，2H)，7.01～7.07(m，2H)。
Embodiment 47:1-(2, the 3-dimethoxy-benzyl)-2-methyl-6,7-dimethoxy-1,2,3, the preparation preparation method of 4-four hydrogen isoquinoline hydrochloric acid salt (51) is with the preparation of compound 50, yield 85.7%.
MS(m/z)：358.2[M+H] +. 1H?NMR(d 6-DMSO)δ2.77(δ，2H，J＝4.5)，2.93～3.07(m，4H)，3.26(s，3H)，3.50～3.61(m，4H)，3.70(s，5H)，3.78(s，3H)，4.47(d，1H，J＝6.6)，5.70(d，1H，J＝6.6)，6.77(d，2H，J＝6.6)，6.81(s，1H)，6.94～7.05(m，2H)，11.44(s，1H)
Embodiment 48:1-(benzo [d] 1 ', 3 '-dioxole-5-yl) methyl-2-methyl-6,8-dimethoxy-1,2,3, the preparation of 4-four hydrogen isoquinoline hydrochloric acid salt (52)
The preparation method is with the preparation of compound 50, yield 79.1%.
MS(m/z)：342.2[M+H] +. 1H?NMR(D 2O)δ2.72(s，3H)，2.92～3.22(m，6H)，3.43(s，1H)，3.65(s，3H)，3.74(s，3H)，5.89(s，2H)，6.54(s，2H)，6.66～6.80(m，5H)。
Embodiment 49:5-(3-bromo-4-methoxy-benzyl)-5,6,7,8-tetrahydrochysene-6-methyl isophthalic acid ', the preparation of 3 '-dioxole [4 ', 5 '-g]-5-isoquinoline hydrochloride (53)
The preparation method is with the preparation of compound 50, yield 87.5%.
MS(m/z)：389.1[M+H] +. 1H?NMR(d 6-DMSO)δ2.73(d，3H，J＝6.0)，2.87～3.08(m，4H)，3.37～3.59(m，2H)，3.83(s，3H)，4.60(s，1H)，5.94(s，1H)，5.96(s，1H)，6.16(s，1H)，6.83(d，1H，J＝6.0)，7.07(d，1H，J＝9.0)，7.17(d，1H，J＝9.0)，7.51(s，1H)，10.41(s，1H)。
Embodiment 50:1-(benzo [d] 1 ', 3 '-dioxole-5-yl) methyl-2-methyl-5,6-dimethoxy-1,2,3, the preparation of 4-four hydrogen isoquinoline hydrochloric acid salt (54)
The preparation method is with the preparation of compound 50, yield 87.5%.
MS(m/z)：342.2[M+H] +. 1H?NMR(d 6-DMSO)δ2.80(d，2H，J＝3.0)，2.94～3.10(m，4H)，3.40～3.60(m，3H)，3.82(s，6H)，4.65(s，1H)，6.07(s，2H)，6.34(d，1H，J＝8.4)，6.66(d，1H，J＝8.4)，6.90(d，1H，J＝8.1)，6.92～7.00(m，3H)，11.16(s，1H)。
Embodiment 51:1-(3-bromo-4-p-methoxy-phenyl) methyl-4-methoxyl group-6-methyl-9-bromo-5,6,7,8-tetrahydrochysene-1 ', the preparation of 3 '-dioxole [4 ', 5 '-g]-5-isoquinoline hydrochloride (55)
The preparation method is with the preparation of compound 50, yield 84.7%.
MS(m/z)：400.2[M+H] +. 1H?NMR(d 6-DMSO)δ2.87(s，2H)，2.98～3.17(m，2H)，3.32～3.44(d，1H)，3.57(s，3H)，3.73～3.84(m，3H)，4.81(s，2H)，6.10(d，2H)，7.09(d，1H)，7.22(d，1H)，7.51(s，1H)，9.92(s，1H)。
Embodiment 52:1-(3,4-two inferior p-methoxy-phenyls) methyl-4-methoxyl group-6-methyl-9-bromo-5,6,7,8-tetrahydrochysene-1 ', the preparation of 3 '-dioxole [4 ', 5 '-g]-5-isoquinoline hydrochloride (56)
The preparation method is with the preparation of compound 50, yield 84.7%.
MS(m/z)：480.2[M+H] +. 1H?NMR(d 6-DMSO)δ2.68(d，3H)，2.86(s，4H)，3.04～3.11(m，2H)，3.65(s，1H)，3.80(s，3H)，4.77(m，1H)，6.00(d，2H)，6.12(s，2H)，6.70(m，1H)，6.82～6.90(m，2H)。
Embodiment 53:(5R)-and 5-(4-methoxy-benzyl)-6-methyl-5,6,7,8-tetrahydrochysene-1 ', the preparation of 3 '-dioxole [4 ', 5 '-g] isoquinoline hydrochloride (57)
The preparation method is with the preparation of compound 50, yield 90.0%.
MS(m/z)：312.1[M+H] +. 1H?NMR(DMSO-d 6)，δ2.50(s，3H)，2.74(m，2H)，2.89，3.04(m，2H)，3.47～3.57(m，2H)，3.74(s，3H)，4.54(m，1H)，5.99(s，2H)，5.92(s，1H)，6.83(s，1H)，6.90(d，2H，J＝8.1Hz)，7.13(d，2H，J＝8.1Hz)，10.86(s，1H)。
Embodiment 54:(5S)-and 5-(4-methoxy-benzyl)-6-ethyl-5,6,7,8-tetrahydrochysene-1 ', the preparation of 3 '-dioxole [4 ', 5 '-g] isoquinoline 99.9 (58)
Under the ice-water bath high degree of agitation, slow of the diethyl ether solution 4mL of Acetyl Chloride 98Min. 2.3mmol, is dripped and finishes in the mixed solution of ether 4.0mL and 5% aqueous sodium carbonate 4.8mL (2.3mmol) to compound 390.5g (1.5mmol), react 10h under the room temperature.Suction filtration, the ether washing gets white solid 0.48g, yield 95.0%.
To go up step gained white solid 0.48g (1.4mmol); sodium borohydride 0.18g (4.2mmol) adds among the tetrahydrofuran (THF) 5.0mL, is warming up to 50 ℃, slowly drips boron trifluoride ether solution 0.57mL (4.2mmol) in the argon shield downhill reaction liquid; drip and finish back flow reaction 3h.Produce a large amount of solid salts in the bottle, reduce to room temperature, add a small amount of diatomite, stir 15min, suction filtration, the tetrahydrofuran (THF) washing is poured filtrate in the frozen water into, transfer to Ph＜2.0 with 2mol/L hydrochloric acid, back flow reaction 1.0h transfers reaction solution to pH＞9.0, ethyl acetate extraction with 10% sodium hydroxide, washing, anhydrous sodium sulfate drying.Suction filtration, concentrating under reduced pressure gets light yellow oil, preparation Thin-layer separation (sherwood oil: ethyl acetate=1: 1), get white solid 0.36g, yield 79.6%.
MS(m/z)：312.1[M+H] +. 1H?NMR(CDCl 3)，δ1.04(t，3H，J＝6.9)，2.64(q，2H，J＝6.9)，2.48，2.71～3.17(m，6H)，3.78(t，4H，J＝4.5)，5.84(d，2H，J＝8.7)，6.15(s，1H)，6.53(s，1H)，7.03(d，2H，J＝8.4)，7.26(d，2H，J＝8.4)。
Embodiment 55:5-(4-methoxy-benzyl)-6-sec.-propyl-5,6,7,8-tetrahydrochysene-1 ', the preparation of 3 '-dioxole [4 ', 5 '-g] isoquinoline hydrochloride (59)
With N-sec.-propyl-N-[2-(benzo [d] 1 ', 3 '-dioxole-5-yl) ethyl]-2-(4-p-methoxy-phenyl) ethanamide 1.8g (5.0mmol) is dissolved among the toluene 14.0mL, add phosphorus oxychloride 7.0mL (50.0mmol) under the stirring at room, slowly be warming up to 80 ℃, reaction 1.0h, concentrating under reduced pressure, with dehydrated alcohol 22.0mL dissolving resistates, slowly add boron sodium oxide 1.0g (25mmol) under-78 ℃ in batches, behind the reaction 3.0h, reaction solution is poured in the weak ammonia into ethyl acetate extraction (20.0mL * 2), washing, anhydrous sodium sulfate drying.Filter, concentrating under reduced pressure gets yellow oil, uses anhydrous alcohol solution, and the ice bath stirring is the dripping hydrochloric acid ethanolic soln down, stirs 2.0h, concentrates, and gets crude product 1.92g, recrystallization (tetrahydrofuran (THF): ethanol=2: 1) get white solid 1.29g, two step yields 70.0%.
MS(m/z)：312.1[M+H] +. 1H?NMR(DMSO-d 6)，δ1.04(d，6H，J＝6.9)，2.96(m，5H)，3.56(m，2H)，3.72(s，3H)，4.62(s，1H)，5.93(t，2H，J＝6.6)，6.07(s，1H)，6.84(s，1H)，6.92(d，2H，J＝8.)，7.28(d，2H，J＝8.7)，10.54(s，1H)。
Embodiment 56:(5R)-and 5-(4-methoxy-benzyl)-6-[(R)-1-styroyl]-5,6,7,8-tetrahydrochysene-1 ', the preparation of 3 '-dioxole [4 ', 5 '-g] isoquinoline 99.9 (60)
(1) N-[(R)-the 1-styroyl]-N-[2-(benzo [d] 1 ', 3 '-dioxole-5-yl) ethyl]-preparation of 2-(4-p-methoxy-phenyl) ethanamide (106)
Under the ice-water bath, the diethyl ether solution 23mL of 4-anisole Acetyl Chloride 98Min. (20.0mmol) is slowly dropped to N-[(R)-the 1-styroyl]-2-(benzo [d] 1 ', 3 '-dioxole-5-yl) ethamine 4.6g (17mmol), in the mixed solution of ether 23.0mL and 5% aqueous sodium carbonate 43mL (20.0mmol), drip and finish, continue reaction 10.0h under the room temperature.Tell organic layer, water layer ether extraction (50mL * 2), combined ether layer, pickling, washing, anhydrous sodium sulfate drying.Filter, concentrating under reduced pressure gets faint yellow oily thing, column chromatography for separation (sherwood oil: ethyl acetate=20: 1), get light yellow oil 6.3g, yield 88.7%.
(2) (R)-and 5-(4-methoxy-benzyl)-6-[(R)-1-styroyl]-5,6,7,8-tetrahydrochysene-1 ', the preparation of 3 '-dioxole [4 ', 5 '-g] isoquinoline 99.9 (60)
Compound (106) 16.7g (40mmol) is dissolved among the toluene 83.5mL, add phosphorus oxychloride 11.4mL (80mmol) under the stirring at room, slowly be warming up to 80 ℃, reaction 1.0h, concentrating under reduced pressure, with dehydrated alcohol 200mL dissolving resistates, slowly add sodium borohydride 7.8g (0.2mol) under-78 ℃, behind the reaction 3h in batches, reaction solution is poured in the weak ammonia, ethyl acetate extraction (60mL * 2), washing, anhydrous sodium sulfate drying.Filter, concentrating under reduced pressure gets yellow oil, uses anhydrous alcohol solution, and ice-water bath stirs 10.0h down, suction filtration, and absolute ethanol washing gets white solid 13.4g, two step yields 82.0%.
MS(m/z)：312.1[M+H] +. 1H?NMR(CDCl 3)，δ1.32(d，3H，J＝8.4)，2.41(m，1H)，2.66(q，1H，J＝6.6)，2.87～3.00(m，2H)，3.22～3.32(m，2H)，3.60～3.70(m，2H)，3.82(s，3H)，5.86(s，2H)，6.10(s，1H)，6.57(s，1H)，6.76(d，2H，J＝8.4Hz)，6.86(d，2H，J＝8.4)，6.95(dd，2H，J＝7.5)，7.09～7.13(m，3H)。
Embodiment 57:(5R)-5-(benzo [d] 1 ', 3 '-dioxole-5-yl) methyl-6-[(R)-the 1-styroyl]-5,6,7,8-tetrahydrochysene-1 ', the preparation of 3 '-dioxole [4 ', 5 '-g] isoquinoline 99.9 (61)
The preparation method is with the preparation of compound 60, yield 80.0%.
MS(m/z)：416.3[M+H] +. 1H?NMR(CDCl 3)，δ1.32(d，3H，J＝8.4Hz)，2.41(m，1H)，2.66(q，1H，J＝6.6)，2.87～3.00(m，2H)，3.22～3.32(m，2H)，3.60～3.70(m，2H)，3.82(s，3H)，5.86(s，2H)，6.56(s，1H)，6.69(s，1H)，6.69(d，1H，J＝6.6)，6.74～6.78(m，2H)，6.95(dd，2H，J＝7.5)，7.09～7.13(m，3H)。
Embodiment 58:5-(2, the 3-dimethoxy-benzyl)-6-normal-butyl-5,6,7,8-tetrahydrochysene-1 ', the preparation of 3 '-dioxole [4 ', 5 '-g]-5-isoquinoline hydrochloride (62)
The fluorine gas protection is also stirred down, and compound 210.72g (2.0mmol) is added to K 2CO 31.06g in the reaction flask of DMF (10.0mmol) (20.0mL), slowly be warming up to 40 ℃, add bromination of n-butane 0.80mL (10.0mmol), reaction 4.0h.Be chilled to room temperature, remove solvent under reduced pressure.Residue is with ethyl acetate (20.0mL * 2) extraction, anhydrous sodium sulfate drying.Filter, concentrate residue, add the acetic acid ethyl fluid 3.0mL of 1.0mol/L hydrogenchloride once more, separate out little yellow solid.Get white solid 0.51g with ethyl alcohol recrystallization, yield 60.8%.
MS(m/z)：383.21[M+H] +. 1H?NMR(D 2O)δ0.83(m，3H)，1.27～1.29(m，2H)，1.74(m，2H)，2.89(m，2H)，2.99(m，2H)，3.59(s，3H)，3.71～3.75(m，2H)，3.80(s，3H)，4.53～4.56(m，1H)，5.88～5.93(m，2H)，6.87～7.02(m，5H)。
Embodiment 59:5-(3, the 4-dimethoxy-benzyl)-6-normal-butyl-5,6,7,8-tetrahydrochysene-1 ', the preparation of 3 '-dioxole [4 ', 5 '-g]-5-isoquinoline hydrochloride (63)
The preparation method is with the preparation of compound 62, yield 80%.
MS(m/z)：383.21[M+H] +. 1H?NMR(d 6-DMSO)δ0.95～1.07(s，3H)，2.81～2.87(m，1H)，2.96～3.04(m，2H)，3.12～3.15(m，1H)，3.28～3.32(m，2H)，3.73(s，3H)，4.63(s，1H)，5.99(d，2H，J＝3.6)，6.42(s，1H)，6.58(s，1H)，6.80(s，1H)，6.86(s，1H)，9.04(s，1H)，9.13(s，1H)。
Embodiment 60:5-(3, the 4-dimethoxy-benzyl)-6-isopentyl-5,6,7,8-tetrahydrochysene-1 ', the preparation of 3 '-dioxole [4 ', 5 '-g]-5-isoquinoline hydrochloride (64)
The preparation method is with the preparation of compound 62, yield 87.2%.
MS(m/z)：383.21[M+H] +. 1H?NMR(d 6-DMSO)δ1.08～1.15(s，3H)，1.17～1.27(s，3H)，2.71～2.81(m，1H)，2.92～3.01(m，2H)，3.08～3.12(m，1H)，3.18～3.22(m，2H)，3.72(s，3H)，4.71(s，1H)，5.77(d，2H，J＝3.6)，6.48(s，1H)，6.55(s，1H)，6.87(s，1H)，6.97(s，1H)。
Embodiment 61:5-(benzo [d] 1 ', 3 '-dioxole-5-yl)-6-normal-butyl-5,6,7,8-tetrahydrochysene-1 ', the preparation of 3 '-dioxole [4 ', 5 '-g] isoquinoline hydrochloride (65)
The preparation method is with the preparation of compound 62, yield 79.7%.
MS(m/z)：368.18[M+H] +. 1H?NMR(D 2O)δ0.87(t，3H，J＝7.03)，0.97(m，1H)，1.23～1.31(m，2H)，1.51(m，1H)，1.75(m，2H)，3.23(d，2H，J＝4.2)，3.40(m，2H)，3.61(m，1H)，3.78(m，1H)，4.66(t，1H，J＝4.2)，5.97(d，4H)，5.99(s，1H)，6.73(d，1H，J＝8.4)，6.81(s，2H)，6.88(d，1H，J＝8.4).
Embodiment 62:5-(2, the 3-dimethoxy-benzyl)-6-ethyl-5,6,7,8-tetrahydrochysene-1 ', the preparation of 3 '-dioxole [4 ', 5 '-g]-5-isoquinoline hydrochloride (66)
The preparation method is with the preparation of compound 62, yield 80.2%.
MS(m/z)：355.18[M+H] +. 1H?NMR(CDCl 3)，δ1.04(t，3H，J＝6.9Hz，CH 3)，2.64(q，2H，J＝6.9Hz，2-CH 2)，2.48&2.71～3.17(m，6H，4-CH 2，3-CH 2，CH 2)，3.78(s，3H，OCH 3)，3.78(m，1H)，5.84(s，2H，O 2CH 2)，6.15(s，1H，5-ArH)，6.53(s，1H，8-ArH)，7.03(d，2H，J＝8.4Hz)，7.26(d，2H，J＝8.4Hz).
Embodiment 63:5-(benzo [d] 1 ', 3 '-dioxole-5-yl)-6-ethyl-5,6,7,8-tetrahydrochysene-1 ', the preparation of 3 '-dioxole [4 ', 5 '-g] isoquinoline hydrochloride (67)
The preparation method is with the preparation of compound 62, yield 89.7%.
MS(m/z)：340.15[M+H] +. 1H?NMR(DMSO)δ1.33(t，3H，J＝6.9)，3.08～3.19(m，4H)，3.27(m，2H)，3.49(m，1H)，3.72(m，1H)，4.69(t，1H，J＝5.3)，5.96(d，4H，J＝2.1)，6.27(s，1H，HCl)，6.68(d，1H，J＝3.6)，6.75(s，2H)，6.80(s，1H)，6.86(d，1H，J＝3.6)。
Embodiment 64:5-(2, the 3-dimethoxy-benzyl)-6-ethyl-5,6,7,8-tetrahydrochysene-1 ', the preparation of 3 '-dioxole [4 ', 5 '-g]-5-isoquinoline hydrochloride (68)
The preparation method is with the preparation of compound 62, yield 78.2%.
MS(m/z)：355.18[M+H] +. 1H?NMR(CDCl 3)δ1.02(t，3H，J＝8.4)，2.4(d，2H，J＝8.4)，2.64～2.74(m，2H)，2.73～2.77(m，2H)，2.81～3.06(m，2H)，3.83(s，6H)，4.29(s，1H)，6.07(m，2H)，6.74～6.91(m，5H)，9.02(s，1H)。
Embodiment 65:5-(2, the 3-dimethoxy-benzyl)-6-isobutyl--5,6,7,8-tetrahydrochysene-1 ', the preparation of 3 '-dioxole [4 ', 5 '-g]-5-isoquinoline hydrochloride (69)
The preparation method is with the preparation of compound 62, yield 87.2%.
MS(m/z)：383.21[M+H] +. 1H?NMR(CDCl 3)，δ1.32(d，3H，J＝8.4Hz)，2.41(m，1H1-CH)，2.66(q，1H，J＝6.6Hz)，2.87～3.00(m，2H，4-CH 2)，3.22～3.32(m，2H，3-CH 2)，3.60～3.70(m，2H，CH 2)，3.82(s，3H，OCH 3)，5.86(s，2H，OCH 2O)，6.56(s，1H，5-ArH)，6.69(s，1H，8-ArH)，6.69(d，1H，J＝6.6Hz，X-ArH)，6.74～6.78(m，2H，A-ArH，B-ArH)，6.95(dd，2H，J＝7.5，1.8Hz)，7.09～7.13(m，3H，3ArH).
Embodiment 66:5-(benzo [d] 1 ', 3 '-dioxole-5-yl)-6-isobutyl--5,6,7,8-tetrahydrochysene-1 ', the preparation of 3 '-dioxole [4 ', 5 '-g] isoquinoline hydrochloride (70)
The preparation method is with the preparation of compound 62, yield 87.4%.
MS(m/z)：367.18[M+H] +. 1H?NMR(D 2O) 1H?NMR(d 6-DMSO)δ2.80(d，2H，J＝3.0)，2.94～3.10(m，4H)，3.40～3.60(m，3H)，3.82(s，6H)，4.65(s，1H)，6.34(d，1H，J＝8.4)，6.66(d，1H，J＝8.4)，6.90(d，1H，J＝8.1)，6.92～7.00(m，3H)，11.16(s，1H)。
Embodiment 67:5-(benzo [d] 1 ', 3 '-dioxole-5-yl)-6-isobutyl--5,6,7,8-tetrahydrochysene-1 ', the preparation of 3 '-dioxole [4 ', 5 '-g]-5-isoquinoline hydrochloride (71)
The preparation method is with the preparation of compound 62, yield 80.2%.
MS(m/z)：383.21[M+H] +. 1H?NMR(CDCl 3)，δ0.80～1.04(m，6H)，1.05(t，3H，J＝6.9)，2.64(q，2H，J＝6.9)，3.78(m，1H)，5.84(s，2H)，5.88(s，2H)，6.15(s，1H)，6.53(s，1H)，7.03(d，2H)，7.26(d，2H)。
Embodiment 68:5-(2, the 3-dimethoxy-benzyl)-6-methyl acetate base-5,6,7,8-tetrahydrochysene-1 ', the preparation of 3 '-dioxole [4 ', 5 '-g]-5-isoquinoline hydrochloride (72)
The preparation method is with the preparation of compound 62, yield 78.5%.
MS(m/z)：355.18[M+H] +? 1H?NMR(CDCl 3)δ2.64～2.74(m，2H)，2.73～2.77(m，2H)，2.81～3.06(m，2H)，3.32(s，2H)，3.68(s，3H)，3.82(s，6H)，4.56(m，1H)，6.07(m，2H)，6.74～6.98(m，5H)，9.03(s，1H)。
Embodiment 69:5-(3, the 4-dimethoxy-benzyl)-6-methyl acetate base-5,6,7,8-tetrahydrochysene-1, the preparation of 3-dioxole [4,5-g] isoquinoline hydrochlorides (73)
The preparation method is with the preparation of compound 62, yield 79.4%.
MS(m/z)：339.18[M+H] +. 1H?NMR(D 2O)δ0.99～1.32(3H)，2.83～2.96(m，2H，4-CH 2)，3.00～3.12(m，1H，3-CH 2)，3.18(m，1H，CH 2)，3.26～3.28(m，1H，3-CH 2)，3.30(m，1H，CH 2)，3.75(s，3H，CH 3)，4.58(m，1H)，5.99(s，2H，O 2CH 2)，6.73(s，1H，5-ArH)，6.80(s，1H，8-ArH)，6.93(d，2H，J＝8.4Hz)，7.28(d，2H，J＝8.4Hz)，9.12(s，2H，NH，HCl).
Embodiment 70:5-(benzo [d] 1 ', 3 '-dioxole-5-yl)-6-methyl acetate base-5,6,7,8-tetrahydrochysene-1 ', the preparation of 3 '-dioxole [4 ', 5 '-g]-5-isoquinoline hydrochloride (74)
The preparation method is with the preparation of compound 62, yield 80.6%.
MS(m/z)：355.18[M+H] +1H?NMR(CDCl 3)δ2.64～2.74(m，2H)，2.73～2.77(m，2H)，2.81～3.06(m，2H)，3.32(s，2H)，3.68(s，3H)，4.55(m，1H)，6.07(m，2H)，6.10(m，2H)，6.74～6.98(m，5H)，9.03(s，1H)。
Embodiment 71:(5,6,7,8-tetrahydrochysene-1 ', 3 '-dioxole [4 ', 5 '-g] isoquinoline 99.9-5-yl) preparation of phenylmethyl acetic acid ester hydrochloride (75)
(1) 2-[2-(benzo [d] 1,3-dioxole-5-yl) ethylamino-]-preparation of 2-oxo-1-phenylmethyl acetic acid ester (107)
In the single port bottle of 250mL, add 10%Na successively 2CO 3The hydrochloride 4.02g (0.02mol) of solution 40mL (0.04mol), 20mL ether, homopiperony lamine.In the single port bottle, slowly drip ether (20.0mL) solution of 2-acetoxyl group-2-phenyl Acetyl Chloride 98Min. 0.02mol under 0 ℃, drip and finish.Room temperature continues to stir 3.0h, separates out white solid.Suction filtration, drying get white solid 6.7g, yield 96.7%.
(2) preparation of (5,6,7,8-tetrahydrochysene-1 ', 3 '-dioxole [4 ', 5 '-g] isoquinoline 99.9-5-yl) phenylmethyl acetic acid ester hydrochloride (75)
In the single port bottle of 100mL, add compound (107) 3.4g (5.0mmol), 25.0mL toluene, 5.0mL (50.0mmol) phosphorus oxychloride successively.Argon shield is stirred 2.0h for following 80 ℃, evaporated under reduced pressure toluene and unnecessary phosphorus oxychloride, the methyl alcohol of adding 30.0mL in bottle.Under 0 ℃ to wherein add NaBH in batches 4(1.14g), finish back room temperature reaction 2.0h.After having reacted the slow impouring of reaction solution is contained in the buck of ice ethyl acetate (30.0mL * 3) extraction, dry, concentrated.In enriched material, add hydrogenchloride ethyl acetate solution salify under the room temperature.Suction filtration, dry white solid 1.28g, the yield 35.5% of getting.
MS(m/z)：325.13[M+H] +. 1H?NMR(D 2O)：δ2.19(s，3H)，2.72(m，1H)，2.87(m，1H)，3.16(m，1H)，3.22(m，1H)，5.00(d，1H，J＝4.8)，6.00(d，2H，J＝6.6)，6.30(d，1H，J＝4.8)，6.70(s，1H)，6.81(s，H)，7.21(d，2H，J＝7.2)，7.35～7.40(m，3H)。
Embodiment 72:(5,6,7,8-tetrahydrochysene-1 ', 3 '-dioxole [4 ', 5 '-g] isoquinoline 99.9-5-yl) preparation of benzyl alcohol hydrochloride (76)
Add compound 750.30g, 2.0mol/LNaOH solution 2.0mL, methyl alcohol 4.0mL in the single port bottle of 50mL successively, 65 ℃ are stirred 6.0h and react completely.Ethyl acetate (15.0mL * 3) extraction, dry, concentrated adds chlorination hydroacetic acid ethyl ester solution salify.Get white solid 0.2g, yield 88.3%.
MS(m/z)：284.1[M+H] +. 1H?NMR(D 2O)：δ2.95(m，2H)，3.41(m，2H)，4.99(d，1H，J＝4.8)，5.53(d，1H，J＝4.8)，6.05(s，2H)，6.56(s，1H)，6.83(s，1H)，7.39(d，2H，J＝3.9)，7.51～7.53(m，3H)。
Embodiment 73:(5,6,7,8-tetrahydrochysene-6-methyl isophthalic acid ', 3 '-dioxole [4 ', 5 '-g] isoquinoline 99.9-5-yl) preparation of phenyl methyl acetic ester hydrochloride (77)
Add compound 750.15g, 37% formaldehyde solution 2.0mL, methyl alcohol 15.0mL in the single port bottle of 50mL successively, stirring at room 6.0h reaction adds NaBH under 0 ℃ in batches 40.24g.Ethyl acetate (15.0mL * 3) extraction, dry, concentrated adds chlorination hydroacetic acid ethyl ester solution salify.Get white solid 0.11g, yield 73..3%.
MS(m/z)：339.15[M+H] +. 1H?NMR(d 6-DMSO)：δ2.06(s，3H)，2.92～2.95(m，5H)，3.15(m，1H)，3.50(m，1H)，4.78(s，1H)5.53(s，1H)，5.91(s，1H)，5.98(s，1H)，6.39(s，1H)，6.86(s，1H)，7.21(d，2H，J＝7.2)，7.32(m，3H)，10.71(s，1H)。
Embodiment 74:(5,6,7,8-tetrahydrochysene-1 ', 3 '-dioxole [4 ', 5 '-g] isoquinoline 99.9-5-yl)-preparation of 1-(3-p-methoxy-phenyl) methyl acetic acid ester hydrochloride (78)
The preparation method gets white solid 0.73g, yield 39.5% with the preparation of compound 75.
MS(m/z)：355.14[M+H] +. 1H?NMR(D 2O)：δ2.25(s，3H)，2.71(m，1H)，2.77(m，1H)，3.17(m，1H)，3.28(m，1H)，3.73(s，3H)，5.05(d，1H，J＝4.6)，6.02(s，2H)，6.32(d，1H，J＝4.6)，6.69(s，1H)，6.77(s，1H)，6.85(s，1H)，6.92(d，1H，J＝7.7)，7.04(d，1H，J＝2.1)，7.37(t，1H，J＝8.1)。
Embodiment 75:(5,6,7,8-tetrahydrochysene-6-methyl isophthalic acid ', 3 '-dioxole [4 ', 5 '-g] isoquinoline 99.9-5-yl)-preparation of 1-(3-p-methoxy-phenyl) methyl acetic acid ester hydrochloride (79)
The preparation method gets white solid 0.87g, yield 48.5% with the preparation of compound 77.
MS(m/z)：355.14[M+H] +. 1H?NMR(D 2O)：δ1.25(s，3H)，2.25(s，3H)，2.71(m，1H)，2.77(m，1H)，3.17(m，1H)，3.28(m，1H)，3.73(s，3H)，5.05(d，1H，J＝4.8)，6.02(s，2H)，6.32(d，1H，J＝4.8)，6.69(s，1H)，6.77(s，1H)，6.85(s，1H)，6.92(d，1H，J＝6.3)，7.03(d，1H，J＝6.3)，7.37(t，1H，J＝5.3)。
Embodiment 76:(5,6,7,8-tetrahydrochysene-1 ', 3 '-dioxole [4 ', 5 '-g] isoquinoline 99.9-5-yl)-preparation of 1-(4-aminomethyl phenyl) methyl acetic acid ester hydrochloride (80)
The preparation method gets white solid 0.11g, yield 42.5% with the preparation of compound 75.
MS(m/z)：339.19[M+H] +. 1H?NMR(D 2O)：δ2.32(s，3H)，2.42(s，3H)，2.85(m，1H)，3.02(m，1H)，3.29(m，1H)，3.33(m，1H)，3.75(m，2H)，5.12(d，1H)，6.11(d，2H)，6.39(d，1H)，6.85(s，1H)，6.96(s，1H)，7.24(d，2H，J＝7.8)，7.34(d，2H，J＝7.8)。
Embodiment 77:(5,6,7,8-tetrahydrochysene-1 ', 3 '-dioxole [4 ', 5 '-g] isoquinoline 99.9-5-yl)-preparation of 1-(3, the 4-Dimethoxyphenyl) methyl acetic acid ester hydrochloride (81)
The preparation method gets white solid 0.15g, yield 48.5% with the preparation of compound 75.
MS(m/z)：385.15[M+H] +. 1H?NMR(d6-DMSO)：δ1.14(s，3H)，(m，1H)，3.32～3.44(m，2H)，3.75(d，6H)，4.57(m，1H)，4.68(d，1H)，5.90～5.98(m，3H)，6.80(d，2H，J＝7.1)，6.95(d，4H)，8.46(s，1H)，9.36(s，1H)。
Embodiment 78:(5,6,7,8-tetrahydrochysene-1 ', 3 '-dioxole [4 ', 5 '-g] isoquinoline 99.9-5-yl)-preparation of 1-(3-p-methoxy-phenyl) methylate hydrochlorate (82)
The preparation method gets white solid 0.09g, yield 81.8% with the preparation of compound 76.
MS(m/z)：329.13[M+H] +. 1H?NMR(D 2O)：δ2.85(m，1H)，3.03(m，1H)，3.40(m，2H)，3.85(s，3H)，4.97(d，1H，J＝4.2)，5.52(d，1H，J＝4.2)，6.06(s，2H)，6.56(s，1H)，6.84(s，1H)，6.87(s，1H)，7.07(m，2H)，7.45(m，1H)。
Embodiment 79:(6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline-1-yl) preparation of phenyl methanol hydrochloride (83)
The preparation method gets white solid 0.10g, yield 76.9% with the preparation of compound 76.
MS(m/z)：335.13[M+H] +. 1H?NMR(D 2O)：δ3.02(m，2H)，3.41(m，2H)，3.63(s，3H)，3.92(s，3H)，5.06(d，1H，J＝3.0)，5.59(d，1H，J＝3.0)，6.36(s，1H)，6.96(s，1H)，7.40(d，2H，J＝7.5)，7.52(m，3H)。
Embodiment 80:(5,6,7-trimethoxy-1,2,3,4-tetrahydroisoquinoline-1-yl)-preparation of 1-(benzo [d] 1 ', 3 '-dioxole-5-yl) methylate hydrochlorate (84)
The preparation method gets white solid 0.12g, yield 82.5% with the preparation of compound 76.
MS(m/z)：409.12[M+H] +. 1H?NMR(D 2O)：δ3.14(m，2H)，3.60(m，4H)，3.75(m，1H)，3.94(s，3H)，3.98(s，3H)，4.72(d，1H，J＝8.4)，5.12(d，1H，J＝8.4)，6.02(s，1H)，6.11(d，2H，J＝7.4)，6.92(d，1H，J＝7.8)，7.02(d，2H，J＝7.8).
Embodiment 81:(5,6,7,8-tetrahydrochysene-6-methyl isophthalic acid ', 3 '-dioxole [4 ', 5 '-g] isoquinoline 99.9-5-yl)-preparation of 1-(4-aminomethyl phenyl) phenylmethyl acetic acid ester hydrochloride (85)
The preparation method gets white solid 0.10g, yield 76.5% with the preparation of compound 76.
MS(m/z)：339.15[M+H] +. 1H?NMR(D 2O)：δ2.27(s，3H)，2.43(s，3H)，2.97(m，1H)，3.10(m，4H)，3.29(m，1H)，3.49(m，1H)，4.99(d，1H，J＝1.8)，6.08(d，2H)，6.31(d，1H，J＝1.8)，6.66(s，1H)，6.89(s，1H)，7.22(d，2H，J＝8.1)，7.36(d，2H，J＝8.1).
Embodiment 82:5-phenyl-3,5,6,11b-tetrahydrochysene-1H-[1 ', 3 '] dioxole [preparation of 4 ', 5 '-g] oxazole [4,3-α] isoquinoline hydrochloride (86)
Add compound 760.15g, Paraformaldehyde 96 0.2g, tosic acid 0.05g, 15.0mL methyl alcohol in the single port bottle of 50mL successively, stirring at room 6.0h reacts completely.In reaction solution impouring buck, ethyl acetate (15.0mL * 3) extraction, dry, concentrated adds hydrogenchloride ethyl acetate solution salify.Get white solid 0.06g, yield 45.1%.
MS(m/z)：295.12[M+H] +. 1H?NMR(CDCl 3)：δ2.63(m，1H)，2.82(m，1H)，3.26(m，1H)，4.58(m，1H)，4.71(d，1H，J＝6.3)，4.89(d，1H，J＝6.3)，5.15(d，1H，J＝8.4)，5.79(s，2H)，6.26(s，1H)，6.44(s，1H)，7.10(m，5H)。
Embodiment 83:1-(3 '-p-methoxy-phenyl)-3,5,6,11b-tetrahydrochysene-1H-[1,3] dioxole [4, the preparation of 5-g] oxazole [4,3-α] isoquinoline hydrochloride (87)
The preparation method gets white solid 0.08g, yield 80.5% with the preparation of compound 82.
MS(m/z)：325.13[M+H] +. 1H?NMR(D 2O)：δ.2.77(m，1H)，2.88(m，1H)，3.33(m，2H)，3.76(s，3H)，4.71(s，2H)，4.81(d，1H，J＝6.9)，5.42(d，1H，J＝6.9)，5.97(s，2H)，6.76(d，2H，J＝8.3)，6.97(m，2H)，7.37(m，1H)。
Embodiment 84:5-(4-p-methoxy-phenyl) ethyl-5,6,7,8-tetrahydrochysene-1 ', the preparation of 3 '-dioxole [4 ', 5 '-g]-5-isoquinoline hydrochloride (88)
The preparation method is with the preparation of compound 76, yield 73.4%.
MS(m/z)：311.15[M+H] +. 1H?NMR(D 2O)δ2.12～2.23(m，2H)，2.64～2.90(m，2H)，2.92～2.97(m，2H)，3.27～3.52(m，2H)，3.73(s，3H)，4.39～4.43(m，1H)，5.87(s，2H)，6.66(d，2H，J＝9.9)，6.88(d，2H，J＝8.6)，7.15(d，2H，J＝8.6)。
Embodiment 85:5-(4-nitrophenyl)-5,6,7,8-four oxygen-1 ', the preparation of 3 '-dioxole [4 ', 5 '-g]-5-isoquinoline hydrochloride (89)
The preparation method is with the preparation of compound 21, yield 78.4%.
MS(m/z)：325.13[M+H] +. 1H?NMR(D 2O)δ2.99～3.42(m，4H)，5.77(s，1H)，5.84(d，2H，J＝7.5)，6.24(s，1H)，6.76(s，1H)，7.50(d，2H，J＝8.4)，8.21(d，2H，J＝8.4)。
Embodiment 86:5-(4-nitrophenyl)-6-methyl-5,6,7,8-tetrahydrochysene-1 ', the preparation of 3 '-dioxole [4 ', 5 '-g]-5-isoquinoline hydrochloride (90)
The preparation method is with the preparation of compound 21, yield 78.4%.
MS(m/z)：325.13[M+H] +. 1H?NMR(D 2O)δ2.82(s，3H)，3.13～3.19(m，2H)，3.39～3.57(m，2H)，5.64(s，1H)，5.85(d，2H，J＝8.1)，6.16(s，1H)，6.77(s，1H)，7.52(d，2H，J＝8.4)，8.25(d，2H，J＝8.4)。
Embodiment 87:5-(4-nitro base phenyl)-6-normal-butyl-5,6,7,8-tetrahydrochysene-1 ', the preparation of 3 '-dioxole [4 ', 5 '-g]-5-isoquinoline hydrochloride (91)
The preparation method is with the preparation of compound 21, yield 74.4%.
MS(m/z)：370.19[M+H] +. 1H?NMR(D 2O)δ0.82(t，3H，J＝7.1)，0.82～1.33(m，2H)，1.66～1.79(m，2H)，3.16～3.58(m，4H)，5.77(s，1H)，5.87(d，2H，J＝7.4)，6.24(s，1H)，6.80(s，1H)，7.52(d，2H，J＝8.2)，8.24(d，2H，J＝8.2)。
Embodiment 88:5-(4-nitro base phenyl)-5,6,7,8-tetrahydrochysene-1 ', the preparation of 3 '-dioxole [4 ', 5 '-g]-5-isoquinoline hydrochloride (92)
The preparation method is with the preparation of compound 21, yield 84.4%.
MS(m/z)：356.10[M+H] +. 1H?NMR(D 2O)δ2.55～2.89(m，2H)，3.64～3.71(m，2H)，3.69(s，3H)，5.48(s，1H)，5.95(d，2H，J＝7.5)，6.28(s，1H)，6.84(s，1H)，7.59(d，2H，J＝9.1)，8.24(d，2H，J＝9.1)。
Embodiment 89:5-(4-nitro base phenyl)-5,6,7,8-tetrahydrochysene-1 ', the preparation of 3 '-dioxole [4 ', 5 '-g]-5-isoquinoline hydrochloride (93)
The preparation method is with the preparation of compound 62, yield 74.4%.
MS(m/z)：370.11[M+H] +. 1H?NMR(D 2O)δ2.44(m，2H)，3.64～3.71(m，2H)，4.39～4.43(m，1H)，5.87(d，2H)，7.55(d，2H)，7.99(d，2H)，8.01(d，2H)。
Embodiment 90:5-(4-nitro base phenyl)-5,6,7,8-tetrahydrochysene-1 ', the preparation of 3 '-dioxole [4 ', 5 '-g]-5-isoquinoline hydrochloride (94)
The preparation method is with the preparation of compound 62, yield 66.4%.
MS(m/z)：370.11[M+H] +. 1H?NMR(D 2O)δ3.09(s，3H)，4.32(d，2H)，5.97(s，1H)，6.40(s，1H)，6.90(s，1H)，7.63(d，2H，J＝8.4)，8.32(d，2H，J＝8.4)。
Embodiment 91:(3R)-and 1-(4-nitro base phenyl)-3-methyl-6,7-dimethoxy-1,2,3, the preparation preparation method of 4-four hydrogen isoquinoline hydrochloric acid salt (95) is with the preparation of compound 62, yield 66.4%.
MS(m/z)：328.14[M+H] +. 1H?NMR(D 2O)δ1.51(t，3H，J＝6.3)，3.09～3.15(q，2H)，3.55(s，3H)，3.88(s，3H)，3.82(m，1H)，5.88(s，1H)，6.26(s，1H)，6.96(s，1H)，7.66(d，2H，J＝8.1)，8.34(d，2H，J＝8.1)。
Embodiment 92:5-ethyl-5,6,7,8-tetrahydrochysene-1 ', the preparation of 3 '-dioxole [4 ', 5 '-g] isoquinoline hydrochloride (96)
The preparation method is with the preparation of compound 21, yield 56.4%.
MS(m/z)：205.11[M+H] +. 1H?NMR(D 2O)：δ0.97(t，3H，J＝7.5)，1.85(m，2H)，2.92(m，2H)，3.32(m，2H)，4.32(t，1H，J＝5.0)，5.88(d，2H，J＝3.1)，6.68(s，1H)，6.73(s，1H)。
Embodiment 93:5-ethyl-6-methyl-5,6,7,8-tetrahydrochysene-1, the preparation preparation method of 3-dioxole [4,5-g] isoquinoline hydrochlorides (97) is with the preparation of compound 50, yield 73.3%.
MS(m/z)：219.12[M+H] +. 1H?NMR(D 2O)：δ0.99(t，3H，J＝7.4)，2.02(m，2H)，2.91(s，3H)，3.05(m，2H)，3.34(m，1H)，3.53～3.70(m，2H)，4.25(t，1H，J＝6.5)，5.95(d，2H，J＝4.3)，6.74～6.77(d，2H，J＝11.5)。
Embodiment 94:5-methyl-5,6,7,8-tetrahydrochysene-1 ', the preparation preparation method of 3 '-dioxole [4 ', 5 '-g]-5-isoquinoline hydrochloride (98) is with the preparation of compound 21, yield 66.1%.
MS(m/z)：191.09[M+H] +. 1H?NMR(D 2O)δ1.53(δ，3H，J＝6.3)，2.89～2.95(m，2H)，3.30(m，H)，3.45(m，H)，4.45(m，H)，5.87(s，2H)，6.67(s，H)，6.72(s，H)。
Embodiment 95:5,6-dimethyl-5,6,7,8-tetrahydrochysene-1 ', the preparation preparation method of 3 '-dioxole [4 ', 5 '-g]-5-isoquinoline hydrochloride (99) is with the preparation of compound 50, yield 82.1%.
MS(m/z)：205.11[M+H] +. 1H?NMR(D 2O)δ1.53(d，3H)，2.89～2.95(m，2H)，3.26～3.49(m，2H)，4.42～4.49(m，1H)，5.87(s，2H)，6.67(s，1H)，6.72(s，1H)。
Embodiment 96:(3R)-1,3-dimethyl-6,7-dimethoxy-1,2,3, the preparation of 4-four hydrogen isoquinoline hydrochloric acid salt (100)
The preparation method is with the preparation of compound 21, yield 77.8%.
MS(m/z)：205.11[M+H] +. 1H?NMR(D 2O)δ1.53(δ，3H，J＝6.3)，1.57(δ，3H，J＝6.3)，2.89～2.95(m，2H)，3.30(m，H)，3.45(m，H)，4.45(m，H)，5.87(s，2H)，6.67(s，H)，6.72(s，H)。
Embodiment 97:5-(tetrahydrofuran (THF)-2-yl)-5,6,7,8-tetrahydrochysene-1 ', the preparation of 3 '-dioxole [4 ', 5 '-g] isoquinoline hydrochloride (101)
(1) preparation of N-(2-(benzo [d] 1 ', 3 '-dioxole-5-yl) ethyl)-1-(tetrahydrofuran (THF)-2-yl) methane amide (108)
In the single port bottle of 250mL, add 10.0%Na successively 2CO 3Solution 0.04mol, 30.0mL ether, homopiperony lamine hydrochloride 4.02g (0.02mol).In the single port bottle, slowly drip ether (10.0mL) solution of tetrahydrofuran (THF)-2-base formyl chloride 0.02mol under 0 ℃, drip and finish, continue to stir 3.0h, separate out white solid.Suction filtration, drying get white solid 4.60g, yield 87.5%.
(2) 5-(tetrahydrofuran (THF)-2-yl)-5,6,7,8-tetrahydrochysene-1 ', the preparation of 3 '-dioxole [4 ', 5 '-g] isoquinoline hydrochloride (101)
In the single port bottle of 100mL, add compound 1080.78g (3.0mmol), toluene 15.0mL, phosphorus oxychloride 0.84mL (9.0mmol) successively.Argon shield is stirred 2.0h for following 80 ℃, and evaporated under reduced pressure toluene and unnecessary phosphorus oxychloride add methyl alcohol 30.0mL in bottle.Under 0 ℃ to wherein add NaBH in batches 40.34g, finish back stirring at room 2.0h.After having reacted the reaction solution impouring is contained in the buck of ice ethyl acetate (30.0mL * 3) extraction, dry, concentrated.In enriched material, add hydrogenchloride ethyl acetate solution salify.Suction filtration, dry white solid 0.53g, the yield 66.8% of getting.
MS(m/z)：247.12[M+H] +. 1H?NMR(D 2O)：δ1.52(m，1H)，1.83(m，2H)，1.95(m，1H)，2.98(m，2H)，3.29(m，1H)，3.52(m，1H)，3.78(m，2H)，4.51(m，1H)，4.67(d，1H，J＝5.0)，5.89(d，2H，J＝6.1)，6.71(s，1H)，6.74(s，1H)。
Embodiment 98:5-(tetrahydrofuran (THF)-2-yl)-6-methyl-5,6,7,8-tetrahydrochysene-1 ', the preparation of 3 '-dioxole [4 ', 5 '-g] isoquinoline hydrochloride (102)
Add compound 1010.23g, 37% formaldehyde solution 2.0mL, methyl alcohol 15.0mL in the single port bottle of 50mL successively, stirring at room 6.0h adds NaBH under 0 ℃ in batches 40.60g.Ethyl acetate (15.0mL * 3) extraction, dry, concentrated adds chlorination hydroacetic acid ethyl ester solution salify.Get white solid 0.19g, yield 81.6%.
MS(m/z)：261.13[M+H] +. 1H?NMR(D 2O)：δ1.93(m，2H)，2.22(m，2H)，3.07(s，3H)，3.15(m，2H)，3.46(s，1H)，3.68(s，1H)，3.89(m，2H)，4.48(s，1H)，4.63(s，1H)，6.06(d，2H，J＝7.8)，6.91(s，2H)。
Embodiment 99: the anti tumor activity in vitro screening
1) cell strain and cell cultures
Cell cultures is in containing 10% (v/v) in the RPMI RPMI-1640 of heat-killed foetal calf serum, 100U/mL penicillin, 100 μ g/mL Streptomycin sulphates and 1mmol/L glutamine, in 37 ℃, 5%CO 2Cultivate in the saturated humidity incubator.
2) the trypan blue method of exclusion is investigated the growth-inhibiting effect of compound pair cell
The subject cell of taking the logarithm vegetative period is with 3 * 10 4The density of/mL is inoculated in 24 orifice plates, 1.0mL in every hole.The administration group added the medicine to be measured (1000 times of dilutions) of respective concentration after inoculation finished, and control group adds 0.1%DMSO.Behind the drug treating 72h, from the cell suspension in every hole, draw mixing in the 0.4% trypan blue solution that 50 μ L cell suspensions add 50 μ L, the mixing liquid that takes a morsel adds blood counting chamber, place under the opticmicroscope and observe, count the cell count in every hole respectively, calculate proliferation inhibition rate and calculate IC according to administration group and cellular control unit number 50
Proliferation inhibition rate %=[1-(administration group cell count/cellular control unit number)] * 100
3) mtt assay is investigated the growth-inhibiting effect of compound pair cell
The adherent tumour cell of taking the logarithm vegetative period is mixed with 5 * 10 4Individual/mL concentration, every hole 100 μ L remove original nutrient solution after being inoculated in 96 orifice plates and cultivating 24h and treat that cell is fully adherent, add the nutrient solution that contains the different concns medicine, every hole 100 μ L, other establishes control group, add the nutrient solution that contains 0.1%DMSO, cultivate 72h for 37 ℃; Finish, careful abandoning supernatant behind 37 ℃ of continuation cultivations of every hole adding 5mg/mL MTT10 μ L 4h, add DMSO 150 μ L/ holes, vibrate 10 minutes with abundant dissolving crystallized thing, measure the OD value at 570nm wavelength place with microplate reader, (Inhibition Rate IR), uses SPSS computed in software half-inhibition concentration (IC again to the inhibiting rate of tumour cell in-vitro multiplication by formula to calculate medicine 50).
Cell proliferation inhibition rate (%)=(1-dosing group OD value/control group OD value) * 100
Test result such as Table 2.
Table 2. compounds are to HL60 human leukocyte Growth Inhibition IC 50Value (μ M, the trypan blue method of exclusion)
Table 3. compounds are to HeLa human cervical carcinoma cell Growth Inhibition IC 50Value (μ M, mtt assay)
Figure G2009102487285D00391
Table 4. compounds are to the inhibiting IC of BEL7402 hepatoma cell growth 50Value (μ M, mtt assay)
Figure G2009102487285D00392
Table 5. compounds are to MCF-7 human breast cancer cell Growth Inhibition IC 50Value (μ M, mtt assay)
Figure G2009102487285D00393
Figure G2009102487285D00401
The result shows that part of compounds of the present invention shows significant proliferation inhibition activity for different knurl strains.

Claims (12)

1. tetrahydroisoquinolicompounds compounds or the acceptable salt of its medicine suc as formula (I):
Figure F2009102487285C00011
Wherein: (a) R 1A kind of in expression hydrogen atom, 1～6 carbon straight chain and branched hydrocarbyl, tetrahydrofuran (THF)-2-base, different benzofuran ketone group or the substituted aryl alkyl;
(b) R 2Expression hydrogen atom, 1～6 carbon straight chain and branched hydrocarbyl ,-COOR 11,-CH 2COOR 11,-CH (CH 3) COOR 11Or-CH 2CH 2COOR 11In a kind of, R wherein 11Be 1～4 carbon straight chain and branched hydrocarbyl;
(c) R 3Expression hydrogen atom, methyl, ethyl ,-COOR 11Or-CH 2COOR 11In a kind of, R wherein 11Be 1～4 carbon straight chain and branched hydrocarbyl;
(d) R 5～R 8A kind of in the substituting groups such as expression hydrogen atom, methoxyl group, oxyethyl group, hydroxyl, difluoro-methoxy, benzyloxy or 1～6 carbon straight chain and branched hydrocarbyl, wherein R 8Can be 1～4 carbon straight chain and branched alkoxy; When on the ring enough electron-donating groups being arranged, R 5～R 8Can partly replace for halogen; Or the consecutive position is with 1, and 3-dioxolane form links to each other as R 5With R 6, R 6With R 7, R 7With R 8For-OCH 2The O-substituting group.
2. the compound described in claim 1 is characterized in that, works as R 1During for different benzofuran ketone group, the structure of following general formula (II) is arranged:
Figure F2009102487285C00012
Wherein: R ' 4～R ' 7A kind of in expression hydrogen atom, methoxyl group, oxyethyl group, hydroxyl, benzyloxy, difluoro-methoxy, hydroxyl methoxyl group, halogen, nitro or 1～6 carbon straight chain and the branched hydrocarbyl; Or the consecutive position is with 1, and 3-dioxolane form links to each other as R ' 4With R ' 5, R ' 5With R ' 6, R ' 6With R ' 7For-OCH 2The O-substituting group.
3. the compound described in claim 1 is characterized in that, works as R 1During for substituted aryl alkyl, the structure of following general formula (III) is arranged:
Figure F2009102487285C00013
Wherein: n=0～2; R ' 4～R ' 8A kind of in the substituting groups such as expression hydrogen atom, methoxyl group, oxyethyl group, hydroxyl, benzyloxy, difluoro-methoxy, hydroxyl methoxyl group, halogen, nitro or 1～6 carbon straight chain and branched hydrocarbyl; Or the consecutive position is with 1, and 3-dioxolane form links to each other as R ' 4With R ' 5, R ' 5With R ' 6, R ' 6With R ' 7For-OCH 2The O-substituting group.
4. the compound described in claim 3 is characterized in that, when n=1, the structure of following general formula (IV) is arranged:
Wherein: R 9A kind of in hydrogen atom, hydroxyl or the acyloxy of expression.
5. the compound described in claim 4 is characterized in that working as R 9Through single step reaction, can obtain the structure of logical formula V during=hydroxyl:
Figure F2009102487285C00021
Wherein: R 10A kind of in expression hydrogen atom, methyl, ethyl, aryl, arylmethyl or the fragrant ethyl.
6. the compound described in claim 1, it is characterized in that acceptable salt is the organic acid salt or the inorganic acid salt of described compound, described organic acid is oxalic acid, succsinic acid, acetic acid, Succinic Acid, toxilic acid, fumaric acid or tartrate, and mineral acid is hydrochloric acid, Hydrogen bromide, hydroiodic acid HI, sulfuric acid or phosphoric acid.
7. any one described compound of claim 1～6 and single optical isomer thereof have the purposes of the inhibition tumor cell proliferation aspect of reported first.
8. the preparation method of tetrahydroisoquinolicompounds compounds as claimed in claim 1, it is characterized in that substituted carboxylic acid compounds VI or its acyl chlorides VII and aminated compounds VIII through condensing agent or the conventional method condensation that forms amido linkage, obtain amides IX, IX is through processing such as phosphorus oxychloride, the Bischler-Napieralski reaction takes place, generate corresponding imines or enamine compound X, X reduces through routine, its reductive agent is sodium borohydride or POTASSIUM BOROHYDRIDE, promptly get target compound Ia after the reduction, or in methyl alcohol, ethanol, THF, with sour salify, obtain salt formula target compound Ia in the organic solvent such as DME or ethyl acetate;
With target compound or its salt Ia with formaldehyde, acetaldehyde, aryl formaldehyde and reductive agent HCOOH, NaBH 4, KBH 4, NaBH 3CN, KBH 3After CN or DIBAL-H handle and carry out hydrocarbylation, obtain target compound Ib or in organic solvents such as methyl alcohol, ethanol, THF, DME or ethyl acetate, obtain the salt Ib of target compound, or directly hydrocarbylation is promptly and R with sour salify 2X reacts under alkaline condition, obtains target compound Ib or obtain the salt Ib of target compound with sour salify in organic solvents such as methyl alcohol, ethanol, THF, DME or ethyl acetate, and wherein the used alkali of this reaction is NEt 3, ( I-Pr) 2NEt, pyridine, NaHCO 3, KHCO 3, Na 2CO 3Or K 2CO 3, solvent for use is N, dinethylformamide, methylene dichloride, ethylene dichloride, chloroform, hexanaphthene, normal hexane, THF, DME or ethyl acetate;
With target compound or its salt Ia and X (CH 2) mCOOR 11React under alkaline condition, obtain target compound Ic, or obtain the salt Ic of target compound with sour salify in organic solvents such as methyl alcohol, ethanol, THF, DME or ethyl acetate, wherein m=0～6 especially 0～2, and the used alkali of this reaction is NEt 3, ( I-Pr) 2NEt, pyridine, NaHCO 3, KHCO 3, Na 2CO 3Or K 2CO 3, solvent for use is N, dinethylformamide, methylene dichloride, ethylene dichloride, chloroform, hexanaphthene, normal hexane, THF, DME or ethyl acetate, wherein R 11Be 1～4 carbon straight chain and branched hydrocarbyl;
Active sulphonate [CH with target compound or its salt Ia and lactic acid or its ester 3(OSO 2R ') COOR 11, R '=Me, CF 3, 4-MeC 6H 4Deng] under alkaline condition, react, obtaining target compound Id or in organic solvents such as methyl alcohol, ethanol, THF, DME or ethyl acetate, obtain the salt Id of target compound with sour salify, the used alkali of this reaction is NaHCO 3, KHCO 3, Na 2CO 3, K 2CO 3, NEt 3, ( I-Pr) 2NEt or pyridine, solvent for use are methylene dichloride, ethylene dichloride, chloroform, hexanaphthene, normal hexane, THF, DME, N, dinethylformamide or ethyl acetate, wherein R 11Be 1～4 carbon straight chain and branched hydrocarbyl.
Figure F2009102487285C00031
9. the preparation method of tetrahydroisoquinolicompounds compounds as claimed in claim 2 is characterized in that formula II type compound has following preparation process:
Figure F2009102487285C00032
10. the preparation method of tetrahydroisoquinolicompounds compounds as claimed in claim 3 is characterized in that the formula III type compound has following preparation process:
11. the preparation method of tetrahydroisoquinolicompounds compounds as claimed in claim 5, it is characterized in that formula IVa compound or its salt with aldehyde compound, in acidic conditions reaction down, form the target product V of similar ethylidene ether structure, or in organic solvents such as methyl alcohol, ethanol, THF, DME or ethyl acetate with sour salify, obtain salt formula target compound V.The acid of this reaction can be methylsulfonic acid, trifluoromethanesulfonic acid, trifluoroacetic acid or tosic acid.Work as R 10During=H, reaction can be adopted Paraformaldehyde 96 or formaldehyde solution; Work as R 10=CH 3The time, reaction can be adopted acetaldehyde, paraldehyde or acetaldehyde solution.
Figure F2009102487285C00042
12. tetrahydroisoquinolicompounds compounds as claimed in claim 1, its preferred compound is:
Figure F2009102487285C00043
Figure F2009102487285C00051
Figure F2009102487285C00071
CN200910248728A 2009-12-24 2009-12-24 Tetrahydroisoquinoline compounds and preparation method and application thereof Pending CN101735229A (en)

Priority Applications (3)

Application Number Priority Date Filing Date Title
CN200910248728A CN101735229A (en) 2009-12-24 2009-12-24 Tetrahydroisoquinoline compounds and preparation method and application thereof
PCT/CN2010/002161 WO2011075957A1 (en) 2009-12-24 2010-12-24 Tetrahydroisoquinoline compounds, preparation methods and uses thereof
CN201010621249.6A CN102134245B (en) 2009-12-24 2010-12-24 Tetralin isoquinoline compounds as well as preparation methods and applications thereof

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN200910248728A CN101735229A (en) 2009-12-24 2009-12-24 Tetrahydroisoquinoline compounds and preparation method and application thereof

Publications (1)

Publication Number Publication Date
CN101735229A true CN101735229A (en) 2010-06-16

Family

ID=42459306

Family Applications (2)

Application Number Title Priority Date Filing Date
CN200910248728A Pending CN101735229A (en) 2009-12-24 2009-12-24 Tetrahydroisoquinoline compounds and preparation method and application thereof
CN201010621249.6A Expired - Fee Related CN102134245B (en) 2009-12-24 2010-12-24 Tetralin isoquinoline compounds as well as preparation methods and applications thereof

Family Applications After (1)

Application Number Title Priority Date Filing Date
CN201010621249.6A Expired - Fee Related CN102134245B (en) 2009-12-24 2010-12-24 Tetralin isoquinoline compounds as well as preparation methods and applications thereof

Country Status (2)

Country Link
CN (2) CN101735229A (en)
WO (1) WO2011075957A1 (en)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011075957A1 (en) * 2009-12-24 2011-06-30 沈阳药科大学 Tetrahydroisoquinoline compounds, preparation methods and uses thereof
CN103214493A (en) * 2013-05-10 2013-07-24 南京友杰医药科技有限公司 Method for generating narcotine by selective reduction utilizing chiral boron catalyst
CN104672136A (en) * 2013-11-30 2015-06-03 沈阳药科大学 1-substituted phenanthryl-N-alkyl (acyl)-6, 7-dimethoxy-1, 2, 3, 4-tetrahydroisoquinoline derivative as well as preparation method and purpose thereof

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013078413A1 (en) * 2011-11-22 2013-05-30 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Modulators of lipid storage
CN103768044B (en) * 2014-01-18 2016-01-20 浙江大学 Suppress the application of the reactive compound of DJ-1 dimerization
CN112480091A (en) * 2020-12-09 2021-03-12 浙江工业大学 Furan ring 2, 5-disubstituted-tetrahydroisoquinoline compound and its preparation and use
CN112552290B (en) * 2020-12-31 2022-10-11 浙江工业大学 Amido bond-containing phenylfuran-2-tetrahydroisoquinoline compound and preparation method and application thereof

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS61165326A (en) * 1985-01-17 1986-07-26 Mitsubishi Chem Ind Ltd Agent for suppressing formation of lipid peroxide, agent for releasing lysozyme and suppressing formation of active oxygen, and agent for suppressing release of histamine
JPH01143833A (en) * 1987-11-30 1989-06-06 Kaken Shiyouyaku Kk Anti-cancer drug
CN101037411B (en) * 2007-03-13 2011-07-06 南京大学 Splitting method of tetrahydroisoquinoline racemes
CN101735229A (en) * 2009-12-24 2010-06-16 沈阳药科大学 Tetrahydroisoquinoline compounds and preparation method and application thereof

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011075957A1 (en) * 2009-12-24 2011-06-30 沈阳药科大学 Tetrahydroisoquinoline compounds, preparation methods and uses thereof
CN102134245A (en) * 2009-12-24 2011-07-27 沈阳药科大学 Tetralin isoquinoline compounds as well as preparation methods and applications thereof
CN102134245B (en) * 2009-12-24 2014-10-29 沈阳药科大学 Tetralin isoquinoline compounds as well as preparation methods and applications thereof
CN103214493A (en) * 2013-05-10 2013-07-24 南京友杰医药科技有限公司 Method for generating narcotine by selective reduction utilizing chiral boron catalyst
CN103214493B (en) * 2013-05-10 2015-12-23 南京友杰医药科技有限公司 The selective reduction of chirality B catalyst is utilized to prepare (-) α-Noscapine
CN104672136A (en) * 2013-11-30 2015-06-03 沈阳药科大学 1-substituted phenanthryl-N-alkyl (acyl)-6, 7-dimethoxy-1, 2, 3, 4-tetrahydroisoquinoline derivative as well as preparation method and purpose thereof
CN104672136B (en) * 2013-11-30 2017-01-25 沈阳药科大学 1-substituted phenanthryl-N-alkyl (acyl)-6, 7-dimethoxy-1, 2, 3, 4-tetrahydroisoquinoline derivative as well as preparation method and purpose thereof
WO2015090216A1 (en) * 2013-12-19 2015-06-25 沈阳药科大学 6, 7-dimethoxy-1, 2, 3, 4-tetrahydroisoquinoline derivative and manufacturing method thereof, pharmaceutical composition comprised thereof, and application thereof

Also Published As

Publication number Publication date
CN102134245B (en) 2014-10-29
CN102134245A (en) 2011-07-27
WO2011075957A1 (en) 2011-06-30

Similar Documents

Publication Publication Date Title
CN102134245B (en) Tetralin isoquinoline compounds as well as preparation methods and applications thereof
CN101195597A (en) 1-substituted-4,4-2 substituted thiosemicarbazide compounds, production method and uses of the same
CN103965118B (en) One class pinane base-2-amino-metadiazine compound and synthetic method thereof and application
US8871802B2 (en) Naphthoquinones for disease therapies
TWI383969B (en) Biphenyl and naphthyl-phenyl hydroxamic acid derivatives
CN110498784B (en) Nobiletin derivatives or pharmaceutically acceptable salts thereof, and preparation method and application thereof
EP2826474B1 (en) Use of substituted diphenylamine compounds in preparing anti-tumour drugs
CN106946868A (en) Nitric oxide donator type coumarin derivative, its preparation method and medical usage
CN103347859A (en) Synthesis and anticancer activity of aryl and heteroaryl-quinolin derivatives
CN103864765B (en) Benzazepine analog derivative containing five-membered ring, Preparation Method And The Use
CN101654401B (en) Asymmetrical biphenyl compounds, medicinal compositions containing same and application of medicinal compositions
CN107573336B (en) Benzoheterocycle-formamide-pyridone derivative and preparation method and application thereof
CN104672136B (en) 1-substituted phenanthryl-N-alkyl (acyl)-6, 7-dimethoxy-1, 2, 3, 4-tetrahydroisoquinoline derivative as well as preparation method and purpose thereof
CA2868508A1 (en) Schweinfurthin analogues
CN1365278A (en) Water soluble trioxanes as potent and safe anti-malarial agents
CN104341407A (en) Quinazoline compounds, preparation method and applications thereof
CN113549046B (en) Bisbecklonin S derivative and preparation method and application thereof
CN111217821B (en) Preparation method of series dioxane quinazoline derivatives
EA003361B1 (en) New compounds of 7-oxo-2,3,7,14-tetrehydro-1h-benzo[b]pyrano[3,2-h]acridine carboxylate and the pharmaceutical compounds containing them
CN103382196B (en) (E)-1-(8-benzopyranyl)-2-propylene-1-ketone and the like and their purposes
CN106432031A (en) Benzoic acid triazole anti-influenza-virus compounds as well as preparation method and application thereof
KR20220104734A (en) Oleanane cinnamamide derivatives, preparation method and use thereof
JP6848047B2 (en) Spiroindron polyethylene glycol carbonate-based compound and its composition, preparation method and its use
CN103058959B (en) N-(2-(4-methylpiperazine-1-yl)-5-formylphenyl) amide compound and application thereof
CN116925055A (en) Coumarin-piperazine-furanone hybrid, and preparation method and application thereof

Legal Events

Date Code Title Description
C06 Publication
PB01 Publication
C02 Deemed withdrawal of patent application after publication (patent law 2001)
WD01 Invention patent application deemed withdrawn after publication

Open date: 20100616