CN102134245A - Tetralin isoquinoline compounds as well as preparation methods and applications thereof - Google Patents
Tetralin isoquinoline compounds as well as preparation methods and applications thereof Download PDFInfo
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- CN102134245A CN102134245A CN2010106212496A CN201010621249A CN102134245A CN 102134245 A CN102134245 A CN 102134245A CN 2010106212496 A CN2010106212496 A CN 2010106212496A CN 201010621249 A CN201010621249 A CN 201010621249A CN 102134245 A CN102134245 A CN 102134245A
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- 0 *C1N(*)C(C(c2c3c(*)c(*)c(*)c2*)OC3=O)c2c(*)c(*)c(*)c(*)c2C1 Chemical compound *C1N(*)C(C(c2c3c(*)c(*)c(*)c2*)OC3=O)c2c(*)c(*)c(*)c(*)c2C1 0.000 description 3
- IOHJRUFWMYLKED-UHFFFAOYSA-N CC1(C)CN(C)C1 Chemical compound CC1(C)CN(C)C1 IOHJRUFWMYLKED-UHFFFAOYSA-N 0.000 description 1
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- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- 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
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- 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
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- 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
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Abstract
The invention relates to tetralin isoquinoline compounds and synthesis thereof as well as applications of the tetralin isoquinoline compounds in the aspect of inhibiting tumor cell proliferation. In the invention, the structure of natural (-)-alpha-(1R, 9S)-narcotine is modified, so as to synthesize a series of novel tetralin isoquinoline compounds (I). In vitro antitumor activity screening indicates that the tetralin isoquinoline compounds have activities of inhibiting the tumor cell proliferation, thus the compounds can be further developed into novel antitumor medicaments.
Description
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.
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.
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., Clin Cancer 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 Biol Chem, 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, Mol Pharmacol, 2003,63,799), the cyclo other compounds that fluorine replaces shows the anti-breast cancer activity stronger than Noscapine (Aneja et 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 et al. 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, 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.
The invention provides a kind of compound or acceptable salt of its medicine suc as formula (I):
Wherein: (a) R
1Be selected from hydrogen atom, C
1-6-alkyl, tetrahydrofuran (THF)-2-base, isobenzofuran ketone group, aryl or aryl-C
1-6A kind of in the-alkyl, wherein said tetrahydrofuran (THF)-2-base, isobenzofuran ketone group, aryl or aryl-C
1-6The substituting group that-alkyl randomly is selected from down group replaces: C
1-6-alkyl, C
1-6--oxyl, hydroxyl, hydroxyl-C
1-6-alkyl, hydroxyl-C
1-6--oxyl, C
1-6-alkylacyloxy, halogen, halo C
1-6-alkyl, halo C
1-6--oxyl, aryl, aryl-C
1-6--oxyl, nitro, amino, C
1-6-alkyl amino or C
1-6-hydrocarbyl amide base;
(b) R
2Be selected from hydrogen atom, C
1-6-alkyl, aryl, aryl-C
1-6-alkyl ,-COOR
11,-CH
2COOR
11,-CH (CH
3) COOR
11Or-CH
2CH
2COOR
11In a kind of, R wherein
11Be C
1-4-alkyl;
(c) R
3Be selected from hydrogen atom, C
1-6-alkyl, aryl, aryl-C
1-6-alkyl ,-COOR
11Or-CH
2COOR
11In a kind of, R wherein
11Be C
1-4-alkyl;
(d) R
5～R
8Be selected from hydrogen atom, C independently of one another
1-6-alkyl, C
1-6--oxyl, hydroxyl, hydroxyl-C
1-6-alkyl, hydroxyl-C
1-6--oxyl, C
1-6-alkylacyloxy, halogen, halo C
1-6-alkyl, halo C
1-6--oxyl, aryl, aryl-C
1-6--oxyl, nitro, amino, C
1-6-alkyl amino or C
1-6A kind of in the-hydrocarbyl amide base, or the R of consecutive position
5With R
6, R
6With R
7Or R
7With R
8For-OCH
2O-is to form 1,3-dioxolane form.
The invention still further relates to the compound or the acceptable salt of its medicine of the structure of following general formula (II):
Wherein: R
2, R
3And R
5～R
8As defined above, R '
4～R '
7Be selected from hydrogen atom, C independently of one another
1-6-alkyl, C
1-6--oxyl, hydroxyl, hydroxyl-C
1-6-alkyl, hydroxyl-C
1-6--oxyl, C
1-6-alkylacyloxy, halogen, halo C
1-6-alkyl, halo C
1-6--oxyl, aryl, aryl-C
1-6--oxyl, nitro, amino, C
1-6-alkyl amino or C
1-6A kind of in the-hydrocarbyl amide base, or the R ' of consecutive position
4With R '
5, R '
5With R '
6Or R '
6With R '
7For-OCH
2O-is to form 1,3-dioxolane form.
The invention still further relates to the compound or the acceptable salt of its medicine of the structure of following general formula (III):
Wherein: n=0～6; R
2, R
3And R
5～R
8As defined above, R '
4～R '
8Be selected from hydrogen atom, C independently of one another
1-6-alkyl, C
1-6--oxyl, hydroxyl, hydroxyl-C
1-6-alkyl, hydroxyl-C
1-6--oxyl, C
1-6-alkylacyloxy, halogen, halo C
1-6-alkyl, halo C
1-6--oxyl, aryl, aryl-C
1-6--oxyl, nitro, amino, C
1-6-alkyl amino or C
1-6A kind of in the-hydrocarbyl amide base, or the R ' of consecutive position
4With R '
5, R '
5With R '
6, R '
6With R '
7Or R '
7With R '
8For-OCH
2O-is to form 1,3-dioxolane form.
The invention still further relates to compound or the acceptable salt of its medicine suc as formula (IV):
Wherein: R
3, R
5～R
8And R '
4～R '
8As defined above, R
9Be selected from hydrogen atom, C
1-6Alkyl, hydroxyl or C
1-6A kind of in the-alkyl acyloxy.
The invention still further relates to compound or the acceptable salt of its medicine as formula V:
Wherein: R
3, R
5～R
8And R '
4～R '
8As defined above, R
10Be selected from hydrogen atom, C
1-6-alkyl, aryl or aryl-C
1-6A kind of in the-alkyl.
The acceptable salt of the medicine of The compounds of this invention is organic acid salt or inorganic acid salt, described organic acid is selected from acetic acid, Succinic Acid, toxilic acid, fumaric acid, tartrate, lactic acid, oxalic acid, methylsulfonic acid, Phenylsulfonic acid, tosic acid or acceptable amino acid, and described mineral acid is selected from hydrochloric acid, Hydrogen bromide, hydroiodic acid HI, sulfuric acid or phosphoric acid.
As used herein, term " aryl " for example is meant monocycle or bicyclic replaces or unsubstituted carbocyclic aromatic group, contain heteroatomic fragrant heterocycles such as nitrogen, sulphur or oxygen.The example of aryl has phenyl, naphthyl etc.
Term " C
1-6-alkyl " be meant the straight or branched with 1-6 carbon atom, saturated or undersaturated alkyl, wherein preferred C
1-6-alkyl.
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 further with itself and sour salify.
Ia or its salt 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 D1BAL-H obtains target compound Ib after handling and carrying out hydrocarbylation, or further with itself and sour salify;
Ia or its salt direct and halo or plan halohydrocarbon R
2Y, Y (CH
2) mCOOR
11, [CH
3CH (Y) COOR
11] hydrocarbyl reaction takes place, obtain target compound Ib～Id, or further with itself and sour salify, wherein m=0～6 especially 0～2, R
11Be C
1-4Alkyl, Y are chlorine, bromine, iodine or OSO
2R ', R
-Be Me, CF
3Or 4-MeC
6H
4
Formula II type compound of the present invention is by preparing as Scheme 2 methods: 1 (the 3H)-different benzene that will replace
A pair of horses going side by side furanone-3-formic acid (XI) is processed into corresponding chloride compounds XII through chlorination reagent.The aminated compounds VIII of XI or XII and replacement obtains 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 sodium borohydride or POTASSIUM BOROHYDRIDE promptly gets target compound IIa, or further with itself and sour salify.
Replace Ia with IIa, respectively with the aldehyde compound reduction amination, or direct and halo or plan halohydrocarbon R
2Y, Y (CH
2) mCOOR
11, [CH
3CH (Y) COOR
11] hydrocarbyl reaction takes place, adopt the similar approach of preparation target compound Ib～Id, similarly can obtain IIb～IId, or further with itself and sour salify.
Formula III type compound of the present invention is by preparing as Scheme 3 methods: with substituted aryl alkanoic acid Ar (CH
2) nCOOH class (XV) is processed into corresponding chloride compounds XVI through chlorination reagent.The aminated compounds VIII of XV or XVI and replacement obtains 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 XVII, generates corresponding imines (or enamine) compounds X VIII.XVIII reduces through routine, and especially reduction such as sodium borohydride or POTASSIUM BOROHYDRIDE promptly gets target compound IIIa, or further with itself and sour salify.
Replace Ia with IIIa, respectively with the aldehyde compound reduction amination, or direct and halo or plan halohydrocarbon R
2Y, Y (CH
2) mCOOR
11, [CH
3CH (Y) COOR
11] hydrocarbyl reaction takes place, adopt the similar approach of preparation target compound Ib～Id, similarly can obtain IIIb～IIId, or further with itself and sour salify.
The preparation method of formula V type compound of the present invention such as Scheme 4: under acidic conditions,, form the compound V of similar ethylidene ether structure with the reaction of formula IVa compound or its salt and aldehydes, or further with itself and sour salify.
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
Preferred compound of the present invention comprises 6,20,21,22,24,26,28,29,30,39,40,41,45,47,48,52,53,56,59,64,80,85,86,87,90 and 91.
The invention still further relates to a kind of pharmaceutical composition, it comprises compound of the present invention and pharmaceutical excipient.
The invention still further relates to above-claimed cpd of the present invention and be used for suppressing the purposes of the medicine of tumor cell proliferation in preparation.
The production of pharmaceutical preparation can be carried out in the mode that any those skilled in the art are familiar with, with the compound of described formula I and/or their pharmaceutical salts, randomly make up other treatment and go up valuable material, go up compatible solid or liquid carrier material and conventional medicinal adjuvant (if desired) with suitable non-toxicity inert treatment and form the galenic form of medication.
The appropriate carriers material not only has inorganic carrier material, and the organic carrier material is arranged.Therefore, lactose for example, the W-Gum or derivatives thereof, talcum, stearic acid or its salt can be used as the carrier substance of tablet, Drug coating, dragee and hard gelatin capsule.Appropriate carriers material for soft gelatin capsule has for example vegetables oil, wax, fat and semisolid and liquid polyol (character that depends on activeconstituents, yet, in the situation of soft gelatin capsule, can not need carrier).Be used to produce solution and syrupy appropriate carriers material has for example water, polyvalent alcohol, sucrose, Nulomoline etc.The suitable carrier substance of injection liquid has for example water, alcohol, polyvalent alcohol, glycerine and vegetables oil.The suitable carrier substance of suppository has for example natural or winterized stearin, wax, fat and semiliquid or liquid polyol.Appropriate carriers material for topical formulations has glyceryl ester, semisynthetic and synthetic glyceryl ester, winterized stearin, liquid wax, whiteruss, liquid aliphatic alcohol, sterols, polyoxyethylene glycol and derivatived cellulose.
Conventional stablizer, sanitas, wetting agent and emulsifying agent, the denseness activator, flavor improving agent, the salt of change osmotic pressure, buffer material, solubilizing agent, tinting material and sequestering agent and antioxidant are considered as the medicine adjuvant.
The dosage of the compound of formula I can change in broad range, and this depends on the disease of control, and patient's age and individual condition, and administering mode will be fit to individual need certainly in each concrete situation.For adult patient, consider the per daily dose of about 0.1mg～10g, particularly about 0.1mg～1.5g.The severity and the accurate pharmacokinetic curve that depend on disease, compound can be with 1 or several per daily dose unit, for example 1～3 dose unit administration.
Pharmaceutical preparation contains the 0.1mg～0.5g that has an appointment expediently, the compound of the formula I of preferred 0.1mg～0.3g.
The following example is used for illustrating in more detail the present invention.Yet they are not to be intended to limit the scope of the invention by any way.
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 have 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), DMAP 0.12g (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 solid.With ethyl alcohol recrystallization, get white solid 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(D
2O)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(D
2O)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 dimethoxys-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(d
6-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)：3422[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 ', 3 '-dioxole | 4, the preparation of 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 ', 3 '-dioxole | 4, the preparation of 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 of 4-four hydrogen isoquinoline hydrochloric acid salt (51)
The preparation method 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 sodium borohydride 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-[(g)-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)
Argon shield 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/L NaOH 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 75 0.15g, 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-tetrahydrochysene-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 of 4-four hydrogen isoquinoline hydrochloric acid salt (95)
The preparation method 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 preparation method of 3 '-dioxole [4 ', 5 '-g] isoquinoline hydrochloride (96) 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 of 3-dioxole [4,5-g] isoquinoline hydrochlorides (97)
The preparation method 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 of 3 '-dioxole [4 ', 5 '-g]-5-isoquinoline hydrochloride (99)
The preparation method 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 (0.02mo1).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 101 0.23g, 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 MTT 10 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)
Table 4. compounds are to the inhibiting IC of BEL7402 hepatoma cell growth
50Value (μ M, mtt assay)
Table 5. compounds are to MCF-7 human breast cancer cell Growth Inhibition IC
50Value (μ M, mtt assay)
The result shows that compound of the present invention shows significant proliferation inhibition activity for different knurl strains.
Claims (15)
1. compound or the acceptable salt of its medicine suc as formula (I):
Wherein: (a) R
1Be selected from hydrogen atom, C
1-6-alkyl, tetrahydrofuran (THF)-2-base, isobenzofuran ketone group, aryl or aryl-C
1-6A kind of in the-alkyl, wherein said tetrahydrofuran (THF)-2-base, isobenzofuran ketone group, aryl or aryl-C
1-6The substituting group that-alkyl randomly is selected from down group replaces: C
1-6-alkyl, C
1-6--oxyl, hydroxyl, hydroxyl-C
1-6-alkyl, hydroxyl-C
1-6--oxyl, C
1-6-alkylacyloxy, halogen, halo C
1-6-alkyl, halo C
1-6--oxyl, aryl, aryl-C
1-6--oxyl, nitro, amino, C
1-6-alkyl amino or C
1-6-hydrocarbyl amide base;
(b) R
2Be selected from hydrogen atom, C
1-6-alkyl, aryl, aryl-C
1-6-alkyl ,-COOR
11,-CH
2COOR
11,-CH (CH
3) COOR
11Or-CH
2CH
2COOR
11In a kind of, R wherein
11Be C
1-4-alkyl;
(c) R
3Be selected from hydrogen atom, C
1-6-alkyl, aryl, aryl-C
1-6-alkyl ,-COOR
11Or-CH
2COOR
11In a kind of, R wherein
11Be C
1-4-alkyl;
(d) R
5～R
8Be selected from hydrogen atom, C independently of one another
1-6-alkyl, C
1-6--oxyl, hydroxyl, hydroxyl-C
1-6-alkyl, hydroxyl-C
1-6--oxyl, C
1-6-alkylacyloxy, halogen, halo C
1-6-alkyl, halo C
1-6--oxyl, aryl, aryl-C
1-6--oxyl, nitro, amino, C
1-6-alkyl amino or C
1-6A kind of in the-hydrocarbyl amide base, or the R of consecutive position
5With R
6, R
6With R
7Or R
7With R
8For-OCH
2O-is to form 1,3-dioxolane form.
2. the compound described in claim 1, it is the structure of following general formula (II):
Wherein: R
2, R
3And R
5～R
8As defined in claim 1, R '
4～R '
7Be selected from hydrogen atom, C independently of one another
1-6-alkyl, C
1-6--oxyl, hydroxyl, hydroxyl-C
1-6-alkyl, hydroxyl-C
1-6--oxyl, C
1-6-alkylacyloxy, halogen, halo C
1-6-alkyl, halo C
1-6--oxyl, aryl, aryl-C
1-6--oxyl, nitro, amino, C
1-6-alkyl amino or C
1-6A kind of in the-hydrocarbyl amide base, or the R ' of consecutive position
4With R '
5, R '
5With R '
6Or R '
6With R '
7For-OCH
2O-is to form 1,3-dioxolane form.
3. the compound described in claim 1, it is the structure of following general formula (III):
Wherein: n=0～6; R
2, R
3And R
5～R
8As defined in claim 1, R '
4～R '
8Be selected from hydrogen atom, C independently of one another
1-6-alkyl, C
1-6--oxyl, hydroxyl, hydroxyl-C
1-6-alkyl, hydroxyl-C
1-6--oxyl, C
1-6-alkylacyloxy, halogen, halo C
1-6-alkyl, halo C
1-6--oxyl, aryl, aryl-C
1-6--oxyl, nitro, amino, C
1-6-alkyl amino or C
1-6A kind of in the-hydrocarbyl amide base, or the R ' of consecutive position
4With R '
5, R '
5With R '
6, R '
6With R '
7Or R '
7With R '
8For-OCH
2O-is to form 1,3-dioxolane form.
4. the compound described in claim 1, it is the structure of following general formula (IV):
Wherein: R
3, R
5～R
8And R '
4～R '
8As defined in claim 1, R
9Be selected from hydrogen atom, C
1-6Alkyl, hydroxyl or C
1-6A kind of in the-alkyl acyloxy.
5. the compound described in claim 1, it is the structure of following logical formula V:
Wherein: R
3, R
5～R
8And R '
4～R '
8As defined in claim 1, R
10Be selected from hydrogen atom, C
1-6-alkyl, aryl or aryl-C
1-6A kind of in the-alkyl.
6. the compound described in claim 1, it is characterized in that the acceptable salt of medicine is organic acid salt or inorganic acid salt, described organic acid is selected from acetic acid, Succinic Acid, toxilic acid, fumaric acid, tartrate, lactic acid, oxalic acid, methylsulfonic acid, Phenylsulfonic acid, tosic acid or acceptable amino acid, and described mineral acid is selected from hydrochloric acid, Hydrogen bromide, hydroiodic acid HI, sulfuric acid or phosphoric acid.
7. as each described compound in the claim 1, it is selected from:
8. a method for preparing Compound I a is characterized in that substituted carboxylic acid class R
1COOH becomes acid amides with amine, generates corresponding imines or enamine through Bischler-Napieralski reaction, promptly gets target compound Ia through reduction again, or further with itself and sour salify,
R wherein
1, R
3And R
5～R
8As each defines in claim 1～claim 5.
9. method for preparing compounds ib is characterized in that carrying out obtaining target compound Ib behind the reductive amination process with Ia or its salt and aldehydes, or further with itself and sour salify,
R wherein
1, R
2, R
3And R
5～R
8As each defines in claim 1～claim 5.
10. method for preparing compounds ib～Id, it is characterized in that with Ia or its salt directly with halo or plan halohydrocarbon R
2Y, Y (CH
2) mCOOR
11, [CH
3CH (Y) COOR
11] hydrocarbyl reaction takes place, obtain target compound Ib～Id, or further with itself and sour salify,
R wherein
1, R
3, R
5～R
8And R
11As each defines in claim 1～claim 5, m=0～6 especially 0～2, Y is chlorine, bromine, iodine or OSO
2R ', R ' are Me, CF
3Or 4-MeC
6H
4
11. a method for preparing Compound I Ia～IId adopts as each described method in claim 8～claim 10, it is characterized in that described R
1COOH replaces to replace 1 (3H)-different benzofuran ketone-3-formic acid class, obtains Compound I Ia～IId,
R wherein
2, R
3, R
5～R
8, R '
4～R '
7And R
11As each defines in claim 1～claim 5, each defines in m such as the claim 10.
12. a method for preparing compound III a～IIId as each described method in claim 8～claim 10, is characterized in that described R
1COOH is with substituted aryl alkanoic acid Ar (CH
2) replacement of nCOOH class, obtain compound III a～IIId,
R wherein
2, R
3, R
5～R
8, R '
4～R '
8, n and R
11As each defines in claim 1～claim 5, each defines in m such as the claim 10.
13. a method for preparing compound V is characterized in that under acidic conditions formula IVa compound or its salt and aldehydes reaction are formed the compound V of similar ethylidene ether structure, or further with itself and sour salify,
R wherein
3, R
5～R
8, R '
4～R '
8And R
10As each defines in claim 1～claim 5.
14. a pharmaceutical composition, it comprises in claim 1～claim 7 each compound and pharmaceutical excipient.
15. each compound is used for suppressing the purposes of the medicine of tumor cell proliferation in claim 1～claim 7 in preparation.
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| CN201010621249.6A Expired - Fee Related CN102134245B (en) | 2009-12-24 | 2010-12-24 | Tetralin isoquinoline compounds as well as preparation methods and applications thereof |
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| CN200910248728A Pending CN101735229A (en) | 2009-12-24 | 2009-12-24 | Tetrahydroisoquinoline compounds and preparation method and application thereof |
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| WO (1) | WO2011075957A1 (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103768044A (en) * | 2014-01-18 | 2014-05-07 | 浙江大学 | Application of active compounds for inhibiting dimerization of DJ-1 |
| 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 |
| CN112552290A (en) * | 2020-12-31 | 2021-03-26 | 浙江工业大学 | Amido bond-containing phenylfuran-2-tetrahydroisoquinoline compound and preparation method and application thereof |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101735229A (en) * | 2009-12-24 | 2010-06-16 | 沈阳药科大学 | Tetrahydroisoquinoline compounds and preparation method and application thereof |
| 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 |
| 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 |
| 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 |
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| CN101735229A (en) * | 2009-12-24 | 2010-06-16 | 沈阳药科大学 | Tetrahydroisoquinoline compounds and preparation method and application thereof |
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- 2009-12-24 CN CN200910248728A patent/CN101735229A/en active Pending
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2010
- 2010-12-24 CN CN201010621249.6A patent/CN102134245B/en not_active Expired - Fee Related
- 2010-12-24 WO PCT/CN2010/002161 patent/WO2011075957A1/en active Application Filing
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| CN101037411A (en) * | 2007-03-13 | 2007-09-19 | 南京大学 | Splitting method of tetrahydroisoquinoline racemes |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103768044A (en) * | 2014-01-18 | 2014-05-07 | 浙江大学 | Application of active compounds for inhibiting dimerization of DJ-1 |
| 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 |
| CN112552290A (en) * | 2020-12-31 | 2021-03-26 | 浙江工业大学 | Amido bond-containing phenylfuran-2-tetrahydroisoquinoline compound and preparation method and application thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| CN101735229A (en) | 2010-06-16 |
| CN102134245B (en) | 2014-10-29 |
| WO2011075957A1 (en) | 2011-06-30 |
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