CN102134245B - 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 PDF

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CN102134245B
CN102134245B CN201010621249.6A CN201010621249A CN102134245B CN 102134245 B CN102134245 B CN 102134245B CN 201010621249 A CN201010621249 A CN 201010621249A CN 102134245 B CN102134245 B CN 102134245B
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CN102134245A (en
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许佑君
魏秀岩
从俊杰
张青扬
倪积智
林禄清
肖和平
韩福庆
王哲
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Shenyang Pharmaceutical University
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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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/02—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines
    • C07D217/04—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines with hydrocarbon or substituted hydrocarbon radicals attached to the ring nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/22—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the nitrogen-containing ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems

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

Tetrahydroisoquinolicompounds compounds and its production and use
Technical field
The invention belongs to the synthetic field of medicine, relate to tetrahydroisoquinolicompounds compounds and preparation method thereof, and the first Application of this compounds aspect inhibition tumor cell propagation.
Background technology
(-)-α-(3S, 5R)-Noscapine belongs to 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]-5-isoquinolyl)-1 (3H)-isobenzofuranone, be classical antitussive medicine, there is toxic side effect low, better tolerance, the feature such as safety range is wide.Meanwhile, Noscapine can be used for treating cerebral apoplexy and oedema.
Joshi seminar (Joshi et al., Proc Natl Acad Sci USA, 1998,95,1601) research discovery in 1998, Noscapine has good anti-tumor activity.Noscapine can stop cell mitogen the phase in M, inducing apoptosis of tumour cell.Experiment in vitro shows, the IC that t cell lymphoma cell E.G7-OVA propagation is suppressed 50value is 10 μ mol/L (Ke et al., Cancer Immunol Immunother, 2000,49,217), the IC that human cervical carcinoma cell Hela propagation is suppressed 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 after 3 weeks, is compared with control group accepting Noscapine (120mg/kg dosage) administration, and tumor control rate is 80%, and check pathological section is not found obvious tissue toxicity.Jaren etc. (Jaren et al., Clin Cancer Res, 2004,10,5187), with immunodeficient mouse model experiment, find that Noscapine reaches 85% to the melanomatous inhibiting rate of B16LS9, to the inhibiting rate of C6 neuroglial tumor cell, are 78%.HPLC detects in the centrifugal supernatant liquor of Mouse Whole Brain homogenate and contains Noscapine, and not only oral absorption is good to show Noscapine, also can pass through hemato encephalic barrier.
Animal experiment shows, Noscapine with various dose, different modes of administration all to the tissues such as the heart, spleen, kidney, duodenum, thymus gland, blood and marrow or organ without any overt toxicity (Ebrahimi et al., Acta Physiol Hung, 2003,90,147).The LD of Noscapine to mouse 50value, for (602 ± 31) mg/kg, can detect temporary transient neurotoxicity (Landen et al., Cancer Res, 2002,62,4109) when 90mg/kg.Humoral immunization and cellular immunization are not had to obvious restraining effect yet, only mucous membrane of small intestine is had to gentle pungency, but do not cause obvious epithelial cell disappearance, when heavy dose of, there are faint hepatotoxicity (Ebrahimi et al., Acta Physiol Hung, 2003,90,147).
Different from 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 ratio of polymer and the monomer of tubulin yet, tubulin dimer=0.95 ± 0.02) and tubulin binding but with stoichiometric ratio (Noscapine molecule:, " the mechanics unstable " that changes microtubule, causes the time lengthening of microtubule in attenuation state (this state microtube length is constant).Microtubule will directly cause the tension force between sister chromosome kinetochore to disappear in attenuation state, and the moment of sister chromosome separation is postponed, and cell is blocked at the M phase of m period.Thereby can induce kinds of tumor cells apoptosis, comprising taxol being produced to the tumour cell (Zhou et al., J Biol Chem, 2002,277,39777) of resistance.
Classical microtubule class medicine affects the fissional while by promoting or suppressing microtubule polymerization, has also had influence on other functions of microtubule, causes the side effect such as nerve and blood widely.And Noscapine only disturbs microtubule dynamic instability, and do not change the ratio of polymer and the monomer of tubulin, do not destroy microtubule " polymerization-depolymerization dynamic circulation " mechanism yet, infer that thus Noscapine is very little for 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 the effect of flesh pine and angst resistance effect, certain analgesic activities.
The structural modification of Noscapine and the antitumor activity of analogue thereof also have report, and the C-9 ' position that the position of modification mainly concentrates on C-1 position, C-7 position and the tetrahydroisoquinoline ring of isobenzofuranone (is the R of patent of the present invention 5position).
(1) C-9 ' position (R 5position) modification on: C-9 ' position H atom with halogen 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 chloro thing is the strongest to the activity of people's glioma brain tumour U87 series cell, 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 active (the Aneja et al. of the anti-breast cancer stronger than Noscapine, Bioorg Med Chem, 2006, 14, 8352).These halo derivatives oral administration biaavailabilities are high, do not find the toxicity to tissues such as the heart, spleen, kidney, duodenum, thymus gland, blood and marrow.And the nitro compound of this position has very strong activity (Aneja et al., Mol Pharmacol, 2006,69,1801) to ovarian cancer, T-Cell lymphoma.Tumour cell to taxol resistance, these compounds are all effective.
(2) modification to C-1 position: parent nucleus isobenzofuranone is replaced with isobenzofuran structure, corresponding compound has than Noscapine more firmly tubulin binding ability and stronger anti-tumor activity, and tumour cell obviously reduces (Zhou et al. to its resistance, Cancer Chemother Pharmacol, 2005,55,461).
(3) modification to C-7 position: people attempt MeO with OH, SH, NH 2and the replacement such as aryl, gained compound still has obvious 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 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 the feature such as other drug drug combination, therefore caused in recent years investigators' keen interest.System is carried out structural modification, this stronger compounds of searching effect, will be significant, and also for finding new antitumoral medicine, lays the foundation.
Summary of the invention
Technical problem solved by the invention is by natural (-)-α-(1R, 9S)-Noscapine is carried out to structure of modification, synthetic a series of tetrahydroisoquinolicompounds compounds (I, II, III, IV and V).By anti tumor activity in vitro, screen, found the compound of many remarkable inhibition tumor cell proliferation activities.For the research of the tumor cell proliferation inhibition activity of these compounds, for the present invention pioneering, so research is significant to exploitation new type antineoplastic medicine.
Another object of the present invention is to provide the preparation method of above-claimed cpd.
The invention provides a kind of compound suc as formula (I) or the acceptable salt of its medicine:
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-alkyl, wherein said tetrahydrofuran (THF)-2-base, isobenzofuran ketone group, aryl or aryl-C 1-6-alkyl is optionally selected from the substituting group of lower group and is replaced: 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 11for 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 11for C 1-4-alkyl;
(d) R 5～R 8be selected from independently of one another hydrogen atom, 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 1-6a kind of in-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 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 independently of one another hydrogen atom, 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 1-6a kind of in-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 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 independently of one another hydrogen atom, 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 1-6a kind of in-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-alkyl acyloxy.
The invention still further relates to as the compound of formula V or the acceptable salt of its medicine:
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-alkyl.
The acceptable salt of 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 " refers to such as replacement or the unsubstituted carbocyclic aromatic group of monocycle or two rings, contains the heteroatomic fragrant heterocycles such as nitrogen, sulphur or oxygen.The example of aryl has phenyl, naphthyl etc.
Term " C 1-6-alkyl " refer to there is the straight or branched of 1-6 carbon atom, saturated or undersaturated alkyl, preferred C wherein 1-6-alkyl.
The preparation method of formula I type compound of the present invention is 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 to amides IX.There is Bischler-Napieralski reaction through processing such as phosphorus oxychloride in IX, generates corresponding imines (or enamine) compounds X.X is through conventional reduction, and especially the reduction such as sodium borohydride or POTASSIUM BOROHYDRIDE obtains target compound Ia, or further by 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 3the reductive agent such as CN or D1BAL-H is processed and to be carried out after hydrocarbylation, obtains target compound Ib, or further by itself and sour salify;
Ia or its salt directly with halo or plan halohydrocarbon R 2y, Y (CH 2) mCOOR 11, [CH 3cH (Y) COOR 11] there is hydrocarbyl reaction, obtain target compound Ib～Id, or further by itself and sour salify, wherein m=0～6 especially 0～2, R 11for C 1-4alkyl, Y is chlorine, bromine, iodine or OSO 2r ', R -for Me, CF 3or 4-MeC 6h 4.
Formula II type compound of the present invention is by preparing as Scheme 2 methods: by 1 (the 3H)-different benzene replacing
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.There is Bischler-Napieralski reaction through processing such as phosphorus oxychloride in XIII, generates corresponding imines (or enamine) compounds X VI.XVI is through conventional reduction, and especially the reduction such as sodium borohydride or POTASSIUM BOROHYDRIDE obtains target compound IIa, or further by itself and sour salify.
With IIa, replace Ia, respectively with aldehyde compound reduction amination, or direct and halo or plan halohydrocarbon R 2y, Y (CH 2) mCOOR 11, [CH 3cH (Y) COOR 11] there is hydrocarbyl reaction, adopt the similar approach of preparing target compound Ib～Id, similarly can obtain IIb～IId, or further by itself and sour salify.
Formula III type compound of the present invention is by preparing as Scheme 3 methods: by 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, through condensing agent or the conventional method condensation that forms amido linkage, obtains amides XVII.There is Bischler-Napieralski reaction through processing such as phosphorus oxychloride in XVII, generates corresponding imines (or enamine) compounds X VIII.XVIII is through conventional reduction, and especially the reduction such as sodium borohydride or POTASSIUM BOROHYDRIDE obtains target compound IIIa, or further by itself and sour salify.
With IIIa, replace Ia, respectively with aldehyde compound reduction amination, or direct and halo or plan halohydrocarbon R 2y, Y (CH 2) mCOOR 11, [CH 3cH (Y) COOR 11] there is hydrocarbyl reaction, adopt the similar approach of preparing target compound Ib～Id, similarly can obtain IIIb～IIId, or further by itself and sour salify.
The preparation method of formula V type compound of the present invention is as Scheme 4: under acidic conditions, formula IVa compound or its salt reacted with aldehydes, forms the compound V of similar ethylidene ether structure, or further by itself and sour salify.
The part target compound of synthesized of the present invention is as table Table 1..
The part target compound of Table 1. synthesizeds of the present invention
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 the purposes of above-claimed cpd of the present invention in the medicine for the preparation of inhibition tumor cell propagation.
The production of pharmaceutical preparation can be carried out in the familiar mode of any those skilled in the art, by the compound of described formula I and/or their pharmaceutical salts, optionally combine the upper valuable material of other treatment, form galenic form of medication with solid or liquid carrier material compatible in the treatment of suitable non-toxicity inertia together with conventional medicinal adjuvant (if needs).
Suitable carrier substance not only has inorganic carrier material, and has organic carrier material.Therefore, lactose for example, 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.Suitable carrier substance 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).Suitable carrier substance for the production of solution and syrup 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.Suitable carrier substance 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, 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 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 applicable 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 for example, with 1 or several per daily dose unit, 1～3 dose unit administration.
Pharmaceutical preparation contains the 0.1mg～0.5g that has an appointment, the preferably compound of the formula I of 0.1mg～0.3g expediently.
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 the tetrahydroisoquinolicompounds compounds (I, II, III, IV and V) of series of new, and its preparation method is simple, favorable reproducibility, and there is the anti-tumor activity that has no preferably bibliographical information.
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-(4,5-methylene-dioxy) styroyl-4, the preparation of 5-dimethoxy-3-oxo-isobenzofuran-1-acid amides (104)
Under argon shield stirring; homopiperony lamine 1.65g (10.0mmol) is slowly splashed in the mixed liquid of 4,5-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 with the mixed liquid of methylene dichloride 20.0mL.Drip and finish, room temperature reaction 12.0h.Filtering insolubles adds water 50mL in reaction solution, divides and gets 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) separation, obtains 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)
Under argon shield stirring, compound 1040.77g (2.0mmol) is heated to 1.5h with the mixed liquid of phosphorus oxychloride 5.0mL (10.0mmol) in 100 ℃.After removing excessive phosphorus oxychloride under reduced pressure, in resistates, add methyl alcohol 20.0mL to destroy residual phosphorus oxychloride, be evaporated to dry.Residue is with methyl alcohol 8.0mL heating for dissolving, the cooling solid of separating out.Suction filtration, is dried to obtain faint yellow solid.
At ice bath and under stirring, above-mentioned faint yellow solid is dissolved in to methyl alcohol 10.0mL, then add sodium borohydride 0.23g (6mmol) in batches.Finish, slowly rise to room temperature and continue reaction 12.0h.With 1.0mol/L hydrochloric acid, adjust pH=1, be evaporated to dry.Add water 10.0mL dispersing and dissolving, with ethyl acetate (5mL * 2) extraction, remove organic impurity.Water layer is adjusted pH=9, with ethyl acetate (10mL * 2), extracts.Merge organic layer, with saturated aqueous common salt (10mL * 2) washing, anhydrous sodium sulfate drying.Filter, concentrate to obtain residue.Ethyl acetate solution 3.0mL salify by this resistates with 1.0mol/L hydrogenchloride, lets cool, and separates out light yellow solid.With ethyl alcohol recrystallization, obtain 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)
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)
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)
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)
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)
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)
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)
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)
Preparation method, 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, obtain 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, 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, the preparation of 5,6-trimethoxy-3-(5,6,7,8-tetrahydrochysene-1 ', 3 '-dioxole [4 ', 5 '-g]-5-isoquinolyl)-1 (3H)-isobenzofuran keto hydrochloride (11)
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)
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 gradually 100 ℃, reaction 8h.Be cooled to room temperature, add the hydrochloric acid 2.0mL of 6.0mol/L, continue to stir 2h.Be evaporated to dryly, in residue, add water 10.0mL, adjust pH=9, with ethyl acetate (10.0mL * 2), extract.Merge organic layer, with saturated aqueous common salt (10mL * 2) washing, anhydrous sodium sulfate drying.Filter, concentrated, gained crude product is after column chromatography for separation, and sterling, with the ethyl acetate solution 2.0mL salify of 1.0mol/L hydrogenchloride, obtains white solid 0.32g, yield 75.3%.
MS(m/z)：384.2[M+H] +. 1H NMR(CDCl 3)δ2.05～2.32(m，1H)，2.55(s，3H)，2.57～2.66(m，2H)，2.88(m，1H)，3.88(s，3H)，3.99(d，1H，J＝3.9)，4.06(s，3H)，5.49(d，1H，J＝3.9)，5.91(s，2H)，6.38(s，1H)，6.51(d，1H，J＝8.2)，6.58(s，1H)，7.07(d，1H，J＝8.2)。
Embodiment 13:5, the preparation of 6 dimethoxy-3 (5,6,7,8-tetrahydrochysene-6-methyl isophthalic acid ', 3 '-dioxole [4 ', 5 '-g]-5-isoquinolyl)-1 (3H)-isobenzofuran keto hydrochloride (14)
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)
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)
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)
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, the preparation of 7-dimethoxy-3-((1S, 3S)-6,7-dimethoxy-2,3-dimethyl-1,2,3,4-tetrahydrochysene-1-isoquinolyl)-1 (3H)-isobenzofuranone (18)
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, the preparation of 7-dimethoxy-3-((1R, 3S)-6,7-dimethoxy-2,3-dimethyl-1,2,3,4-tetrahydrochysene-1-isoquinolyl)-1 (3H)-isobenzofuran keto hydrochloride (19)
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)
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-(2,3-veratryl)-5,6,7,8-tetrahydrochysene-1 ', the preparation of 3 '-dioxole [4 ', 5 '-g]-5-isoquinoline hydrochloride (21)
(1) preparation of N-(2-(4,5-methylenedioxyphenyl) ethyl)-2-(2,3-Dimethoxyphenyl) ethanamide (105)
Under argon shield stirring, the mixed liquid heating reflux reaction 4.0h by homopiperony lamine 1.96g (0.01mol) with thionyl chloride 5.0mL.Concentrating under reduced pressure, residue dissolves with ether 20.0mL.Under ice bath stirring, this diethyl ether solution is slowly dropped in the mixed liquid of compound 11.65g (0.01mol), ether 20.0mL and 6.0% sodium carbonate solution 20.0mL, separate out gradually white solid.Drip and finish, continue to stir 1.0h.Suction filtration, dry, obtain solid 2.7g, yield 78.0%.
(2) 5-(2,3-veratryl)-5,6,7,8-tetrahydrochysene-1 ', the preparation of 3 '-dioxole [4 ', 5 '-g]-5-isoquinoline hydrochloride (21)
Under argon shield stirring, the 100 ℃ of reacting by heating 1.5h of mixed liquid by compound 105 0.68g (2.0mmol) with phosphorus oxychloride 5.0mL (10.0mmol).After removing excessive phosphorus oxychloride under reduced pressure, in resistates, add methyl alcohol 20.0mL to destroy residual phosphorus oxychloride, be evaporated to dry.Residue is with methyl alcohol 8.0mL heating for dissolving, the cooling solid of separating out.Suction filtration, is dried to obtain faint yellow solid.
At ice bath and under stirring, above-mentioned faint yellow solid is dissolved in to methyl alcohol 20mL, then add sodium borohydride 0.23g (6mmol) in batches.Finish, slowly rise to room temperature and continue reaction 12.0h.With 1.0mol/L hydrochloric acid, adjust pH=1.0, be evaporated to dry.Add water 10.0mL dispersing and dissolving, with ethyl acetate (5mL * 2) extraction, remove organic impurity.Water layer is adjusted pH=9, with ethyl acetate (10mL * 2) extraction, anhydrous sodium sulfate drying.Filter, concentrate to obtain residue.Acetic acid ethyl fluid 3.0mL heating dispersing and dissolving by this resistates with 1.0mol/L HCl, lets cool, and separates out light yellow solid.With ethyl alcohol recrystallization, obtain 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-(2,3-dimethoxy-benzyl)-5,6-dimethoxy-1, the preparation preparation method of 2,3,4-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-(2,3-dimethoxy-benzyl)-6,7-dimethoxy-1, the preparation of 2,3,4-four hydrogen isoquinoline hydrochloric acid salt (23)
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-(3,5-dimethoxy-benzyl)-5,6,7,8-tetrahydrochysene-1 ', the preparation of 3 '-dioxole [4 ', 5 '-g]-5-isoquinoline hydrochloride (24)
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, the preparation of 2,3,4-four hydrogen isoquinoline hydrochloric acid salt (25)
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, the preparation of 2,3,4-four hydrogen isoquinoline hydrochloric acid salt (26)
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, the preparation of 2,3,4-four hydrogen isoquinoline hydrochloric acid salt (27)
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-(the bromo-4-methoxy-benzyl of 3-)-5,6,7,8-tetrahydrochysene-1 ', the preparation of 3 '-dioxole [4 ', 5 '-g]-5-isoquinoline hydrochloride (28)
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-(the bromo-4-methoxy-benzyl of 3-) methyl-6,8-dimethoxy-1, the preparation of 2,3,4-four hydrogen isoquinoline hydrochloric acid salt (29)
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)-1-(the bromo-4-methoxy-benzyl of 3-) methyl-3-methyl-6,7-dimethoxy-1, the preparation of 2,3,4-four hydrogen isoquinoline hydrochloric acid salt (30)
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)-1-(benzo [d] 1 ', 3 '-dioxole-5-yl) methyl-3-methyl-6,7-dimethoxy-1, the preparation of 2,3,4-four hydrogen isoquinoline hydrochloric acid salt (31)
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)-1-(2,3-dimethoxy-benzyl) methyl-3-methyl-6,7-dimethoxy-1, the preparation of 2,3,4-four hydrogen isoquinoline hydrochloric acid salt (32)
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)-1-(benzo [d] 1 ', 3 '-dioxole-5-yl) methyl-3-methyl-7-methoxyl group-1, the preparation of 2,3,4-four hydrogen isoquinoline hydrochloric acid salt (33)
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)-1-(4-methoxy-benzyl)-3-methyl-7-methoxyl group-1, the preparation of 2,3,4-four hydrogen isoquinoline hydrochloric acid salt (34)
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)-1-(the bromo-4-methoxy-benzyl of 3-) methyl-3-methyl-6,7-dimethoxy-1, the preparation of 2,3,4-four hydrogen isoquinoline hydrochloric acid salt (35)
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)-1-(benzo [d] 1 ', 3 '-dioxole-5-yl) methyl-3-methyl-6,7-dimethoxy-1, the preparation of 2,3,4-four hydrogen isoquinoline hydrochloric acid salt (36)
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)-1-(2,3-dimethoxy-benzyl) methyl-3-methyl-6,7-dimethoxy-1, the preparation of 2,3,4-four hydrogen isoquinoline hydrochloric acid salt (37)
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)-1-(3,4-Dimethoxyphenyl) methyl-3-methyl-6,7-dimethoxy-1, the preparation of 2,3,4-four hydrogen isoquinoline hydrochloric acid salt (38)
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 ', the preparation of 3 '-dioxole [4 ', 5 '-g] isoquinoline hydrochloride (40)
Preparation method, with the preparation of compound 21, obtains the free alkali of compound through column chromatography for separation, under ice bath, obtain compound 39 and compound 40, total recovery 78.0% respectively with hydrogenchloride ethyl acetate solution salify.
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)
Preparation method, with the preparation of compound 21, obtains the free alkali of compound through column chromatography for separation, under ice bath, obtain compound 41 and compound 42, total recovery 73% respectively with hydrogenchloride ethyl acetate solution salify.
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-(3,4-dimethoxy-benzyl)-5,6,7,8-tetrahydrochysene-1 ', 3 '-dioxole [4 ', 5 '-g] isoquinoline hydrochloride (43) and (5S)-5-(3,4-dimethoxy-benzyl)-5,6,7,8-tetrahydrochysene-1 ', the preparation of 3 '-dioxole [4 ', 5 '-g] isoquinoline hydrochloride (44)
Preparation method, with the preparation of compound 21, obtains the free alkali of compound through column chromatography for separation, under ice bath, obtain compound 43 and compound 44, total recovery 71.0% respectively with hydrogenchloride ethyl acetate solution salify.
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)
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 mixed liquid of compound 452.0g (5.0mmol), 10% palladium charcoal 0.2g and ethanol 40.0mL, cut the hydrogen of 3atm, room temperature vigorous stirring catalytic hydrogenation 48h.Filtering palladium charcoal, concentrating under reduced pressure, resistates, through re-crystallizing in ethyl acetate, obtains white solid 1.08g, yield 68.0%.
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)，9.20(s，1H，HCl)。
Embodiment 43:1-(the sub-p-methoxy-phenyl of 3,4-bis-) methyl-4-methoxyl group-9-is bromo-5,6,7,8-tetrahydrochysene-1 ', the preparation of 3 '-dioxole [4,5-g]-5-isoquinoline hydrochloride (47)
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-(the bromo-4-p-methoxy-phenyl of 3-) methyl-4-methoxyl group-9-is bromo-5,6,7,8-tetrahydrochysene-1 ', and 3 '-dioxole | the preparation of 4,5-g|-5-isoquinoline hydrochloride (48)
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-(4,5-Dimethoxyphenyl) methyl-6-methyl-9-is bromo-5,6,7,8-tetrahydrochysene-1 ', and 3 '-dioxole | the preparation of 4,5-g|-5-isoquinoline hydrochloride (49)
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-(2,3-dimethoxy-benzyl)-6-methyl-5,6,7,8-tetrahydrochysene-1 ', the preparation of 3 '-dioxole [4 ', 5 '-g]-5-isoquinoline hydrochloride (50)
Under agitation, by the mixed liquid room temperature reaction 5.0h of compound 210.18g (0.5mmol), 37% formaldehyde solution 0.5mL (7.0mmol) and methyl alcohol 2.0mL, cooling through ice bath again, in this mixed liquid, add sodium borohydride 0.23g (6.0mmol) in batches.Finish, continue stirring reaction 8.0h.Add water 10.0mL, with ethyl acetate (10mL * 2) extraction, merge organic phase, anhydrous sodium sulfate drying.Filter, concentrated, gained crude product is separated through silica gel column chromatography, obtain oily matter again under ice bath the acetic acid ethyl fluid with hydrogenchloride process salify, obtain 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-(2,3-dimethoxy-benzyl)-2-methyl-6,7-dimethoxy-1, the preparation of 2,3,4-four hydrogen isoquinoline hydrochloric acid salt (51)
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, the preparation of 2,3,4-four hydrogen isoquinoline hydrochloric acid salt (52)
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-(the bromo-4-methoxy-benzyl of 3-)-5,6,7,8-tetrahydrochysene-6-methyl isophthalic acid ', the preparation of 3 '-dioxole [4 ', 5 '-g]-5-isoquinoline hydrochloride (53)
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, the preparation of 2,3,4-four hydrogen isoquinoline hydrochloric acid salt (54)
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-(the bromo-4-p-methoxy-phenyl of 3-) methyl-4-methoxyl group-6-methyl-9-is bromo-5,6,7,8-tetrahydrochysene-1 ', the preparation of 3 '-dioxole [4 ', 5 '-g]-5-isoquinoline hydrochloride (55)
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-(the sub-p-methoxy-phenyl of 3,4-bis-) methyl-4-methoxyl group-6-methyl-9-is bromo-5,6,7,8-tetrahydrochysene-1 ', the preparation of 3 '-dioxole [4 ', 5 '-g]-5-isoquinoline hydrochloride (56)
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)-5-(4-methoxy-benzyl)-6-methyl-5,6,7,8-tetrahydrochysene-1 ', the preparation of 3 '-dioxole [4 ', 5 '-g] isoquinoline hydrochloride (57)
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)-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 ice-water bath high degree of agitation, the diethyl ether solution 4mL of Acetyl Chloride 98Min. 2.3mmol is slowly dropped to compound 390.5g (1.5mmol), in the mixed solution of ether 4.0mL and 5% aqueous sodium carbonate 4.8mL (2.3mmol), drip and finish, under room temperature, react 10h.Suction filtration, ether washing, obtains white solid 0.48g, yield 95.0%.
By upper step gained white solid 0.48g (1.4mmol); sodium borohydride 0.18g (4.2mmol) adds in tetrahydrofuran (THF) 5.0mL, is warming up to 50 ℃, slowly drips boron trifluoride ether solution 0.57mL (4.2mmol) in argon shield downhill reaction liquid; drip and finish, back flow reaction 3h.In bottle, produce a large amount of solid salts, be down to room temperature, add a small amount of diatomite, stir 15min, suction filtration, tetrahydrofuran (THF) washing, pours filtrate in frozen water into, with 2mol/L hydrochloric acid, be adjusted to Ph < 2.0, back flow reaction 1.0h, adjusts reaction solution to pH > 9.0 with 10% sodium hydroxide, ethyl acetate extraction, washing, anhydrous sodium sulfate drying.Suction filtration, concentrating under reduced pressure, obtains light yellow oil, the separated (sherwood oil: ethyl acetate=1: 1), obtain white solid 0.36g, yield 79.6% of Preparative TLC.
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)
By 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 in toluene 14.0mL, under stirring at room, add phosphorus oxychloride 7.0mL (50.0mmol), slowly be warming up to 80 ℃, reaction 1.0h, concentrating under reduced pressure, with dehydrated alcohol 22.0mL, dissolve resistates, at-78 ℃, slowly add sodium borohydride 1.0g (25mmol) in batches, after reaction 3.0h, reaction solution is poured in weak ammonia into ethyl acetate extraction (20.0mL * 2), washing, anhydrous sodium sulfate drying.Filter, concentrating under reduced pressure, obtains yellow oil, with anhydrous alcohol solution, ice bath stirs the lower ethanol solution hydrochloride that drips, and stirs 2.0h, concentrated, obtain crude product 1.92g, recrystallization (tetrahydrofuran (THF): ethanol=2: 1) obtain 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)-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)-1-styroyl]-N-[2-(benzo [d] 1 ', 3 '-dioxole-5-yl) ethyl] preparation of-2-(4-p-methoxy-phenyl) ethanamide (106)
Under ice-water bath, the diethyl ether solution 23mL of 4-anisole Acetyl Chloride 98Min. (20.0mmol) is slowly dropped to N-[(R)-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, under room temperature, continue reaction 10.0h.Separate organic layer, ether extraction for water layer (50mL * 2), combined ether layer, pickling, washing, anhydrous sodium sulfate drying.Filter, concentrating under reduced pressure, obtains faint yellow oily matter, column chromatography for separation (sherwood oil: ethyl acetate=20: 1), obtain light yellow oil 6.3g, yield 88.7%.
(2) (R)-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 in toluene 83.5mL, under stirring at room, add phosphorus oxychloride 11.4mL (80mmol), be slowly warming up to 80 ℃, reaction 1.0h, concentrating under reduced pressure, with dehydrated alcohol 200mL, dissolve resistates, slowly add sodium borohydride 7.8g (0.2mol) at-78 ℃, after reaction 3h in batches, reaction solution is poured in weak ammonia, ethyl acetate extraction (60mL * 2), washing, anhydrous sodium sulfate drying.Filter, concentrating under reduced pressure, obtains yellow oil, with anhydrous alcohol solution, under ice-water bath, stirs 10.0h, suction filtration, and absolute ethanol washing, obtains 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)-1-styroyl]-5,6,7,8-tetrahydrochysene-1 ', the preparation of 3 '-dioxole [4 ', 5 '-g] isoquinoline 99.9 (61)
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-(2,3-dimethoxy-benzyl)-6-normal-butyl-5,6,7,8-tetrahydrochysene-1 ', the preparation of 3 '-dioxole [4 ', 5 '-g]-5-isoquinoline hydrochloride (62)
Under argon shield stirring, compound 210.72g (2.0mmol) is added to K 2cO 3in the reaction flask of the DMF (20.0mL) of 1.06g (10.0mmol), be slowly 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 to obtain residue, again add the acetic acid ethyl fluid 3.0mL of 1.0mol/L hydrogenchloride, separate out micro-yellow solid.With ethyl alcohol recrystallization, obtain white solid 0.51g, 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-(3,4-dimethoxy-benzyl)-6-normal-butyl-5,6,7,8-tetrahydrochysene-1 ', the preparation of 3 '-dioxole [4 ', 5 '-g]-5-isoquinoline hydrochloride (63)
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-(3,4-dimethoxy-benzyl)-6-isopentyl-5,6,7,8-tetrahydrochysene-1 ', the preparation of 3 '-dioxole [4 ', 5 '-g]-5-isoquinoline hydrochloride (64)
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)
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-(2,3-dimethoxy-benzyl)-6-ethyl-5,6,7,8-tetrahydrochysene-1 ', the preparation of 3 '-dioxole [4 ', 5 '-g]-5-isoquinoline hydrochloride (66)
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)
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-(2,3-dimethoxy-benzyl)-6-ethyl-5,6,7,8-tetrahydrochysene-1 ', the preparation of 3 '-dioxole [4 ', 5 '-g]-5-isoquinoline hydrochloride (68)
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-(2,3-dimethoxy-benzyl)-6-isobutyl--5,6,7,8-tetrahydrochysene-1 ', the preparation of 3 '-dioxole [4 ', 5 '-g]-5-isoquinoline hydrochloride (69)
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)
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)
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-(2,3-dimethoxy-benzyl)-6-methyl acetate base-5,6,7,8-tetrahydrochysene-1 ', the preparation of 3 '-dioxole [4 ', 5 '-g]-5-isoquinoline hydrochloride (72)
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-(3,4-dimethoxy-benzyl)-6-methyl acetate base-5, the preparation of 6,7,8-tetrahydro-1,3 dioxa cyclopentenes [4,5-g] isoquinoline hydrochloride (73)
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)
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 successively 10%Na 2cO 3the hydrochloride 4.02g (0.02mol) of solution 40mL (0.04mol), 20mL ether, homopiperony lamine.At 0 ℃, to ether (20.0mL) solution that slowly drips 2-acetoxyl group-2-phenylacetyl chlorine 0.02mol in single port bottle, drip and finish.Room temperature continues to stir 3.0h, separates out white solid.Suction filtration, dry, obtains 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 successively compound (107) 3.4g (5.0mmol), 25.0mL toluene, 5.0mL (50.0mmol) phosphorus oxychloride.2.0h are stirred in lower 80 ℃ of argon shield, and evaporated under reduced pressure toluene and unnecessary phosphorus oxychloride, to the methyl alcohol that adds 30.0mL in bottle.At 0 ℃, add wherein NaBH in batches 4(1.14g), finish rear room temperature reaction 2.0h.In the buck that after having reacted, the slow impouring of reaction solution has been contained to ice, ethyl acetate (30.0mL * 3) extraction, dry, concentrated.Under room temperature, in enriched material, add hydrogenchloride ethyl acetate solution salify.Suction filtration, dry white solid 1.28g, the yield 35.5% of obtaining.
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)
In the single port bottle of 50mL, add successively compound 750.30g, 2.0mol/L NaOH solution 2.0mL, methyl alcohol 4.0mL, 65 ℃ are stirred 6.0h and react completely.Ethyl acetate (15.0mL * 3) extraction, dry, concentrated, adds chlorination hydroacetic acid ethyl ester solution salify.Obtain 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)
In the single port bottle of 50mL, add successively compound 75 0.15g, 37% formaldehyde solution 2.0mL, methyl alcohol 15.0mL, stirring at room 6.0h reaction adds NaBH at 0 ℃ in batches 40.24g.Ethyl acetate (15.0mL * 3) extraction, dry, concentrated, adds chlorination hydroacetic acid ethyl ester solution salify.Obtain 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)
Preparation method, with the preparation of compound 75, obtains white solid 0.73g, yield 39.5%.
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)
Preparation method, with the preparation of compound 77, obtains white solid 0.87g, yield 48.5%.
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)
Preparation method, with the preparation of compound 75, obtains white solid 0.11g, yield 42.5%.
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-(3,4-Dimethoxyphenyl) methyl acetic acid ester hydrochloride (81)
Preparation method, with the preparation of compound 75, obtains white solid 0.15g, yield 48.5%.
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)
Preparation method, with the preparation of compound 76, obtains white solid 0.09g, yield 81.8%.
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)
Preparation method, with the preparation of compound 76, obtains white solid 0.10g, yield 76.9%.
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)
Preparation method, with the preparation of compound 76, obtains white solid 0.12g, yield 82.5%.
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)
Preparation method, with the preparation of compound 76, obtains white solid 0.10g, yield 76.5%.
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)
In the single port bottle of 50mL, add successively compound 760.15g, paraformaldehyde 0.2g, tosic acid 0.05g, 15.0mL methyl alcohol, stirring at room 6.0h, reacts completely.By in reaction solution impouring buck, ethyl acetate (15.0mL * 3) extraction, dry, concentrated, adds hydrogenchloride ethyl acetate solution salify.Obtain 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 [preparation of 4,5-g] oxazole [4,3-α] isoquinoline hydrochloride (87)
Preparation method, with the preparation of compound 82, obtains white solid 0.08g, yield 80.5%.
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)
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)
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)
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)
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)
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)
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)
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)-1-(4-nitro base phenyl)-3-methyl-6,7-dimethoxy-1, the preparation of 2,3,4-four hydrogen isoquinoline hydrochloric acid salt (95)
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, the preparation of 6,7,8-tetrahydro-1,3 dioxa cyclopentenes [4,5-g] isoquinoline hydrochloride (97)
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)
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, the preparation of 2,3,4-four hydrogen isoquinoline hydrochloric acid salt (100)
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 successively 10.0%Na 2cO 3solution 0.04mol, 30.0mL ether, homopiperony lamine hydrochloride 4.02g (0.02mo1).At 0 ℃, to slowly dripping ether (10.0mL) solution of tetrahydrofuran (THF)-2-base formyl chloride 0.02mol in single port bottle, drip and finish, continue to stir 3.0h, separate out white solid.Suction filtration, dry, obtains 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 successively compound 1080.78g (3.0mmol), toluene 15.0mL, phosphorus oxychloride 0.84mL (9.0mmol).The lower 80 ℃ of stirring 2.0h of argon shield, evaporated under reduced pressure toluene and unnecessary phosphorus oxychloride add methyl alcohol 30.0mL in bottle.At 0 ℃, add wherein NaBH in batches 40.34g, finishes rear stirring at room 2.0h.In the buck that after having reacted, reaction solution impouring has been contained to 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 obtaining.
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)
In the single port bottle of 50mL, add successively compound 101 0.23g, 37% formaldehyde solution 2.0mL, methyl alcohol 15.0mL, stirring at room 6.0h adds NaBH at 0 ℃ in batches 40.60g.Ethyl acetate (15.0mL * 3) extraction, dry, concentrated, adds chlorination hydroacetic acid ethyl ester solution salify.Obtain 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: 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 2in saturated humidity incubator, cultivate.
2) the trypan blue method of exclusion is investigated the growth-inhibiting effect of compound to cell
The subject cell of taking the logarithm vegetative period, with 3 * 10 4the density of/mL is inoculated in 24 orifice plates, 1.0mL in every hole.After inoculation, administration group adds the medicine to be measured (1000 times of dilutions) of respective concentration, and control group adds 0.1%DMSO.After drug treating 72h, from the cell suspension in every hole, draw in the 0.4% trypan blue solution that 50 μ L cell suspensions add 50 μ L and mix, take a morsel and mix liquid and add blood counting chamber, be placed in optical microphotograph Microscopic observation, count respectively the cell count in every hole, according to administration group and cellular control unit number, calculate proliferation inhibition rate and calculate IC 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 to cell
The adherent tumour cell of taking the logarithm vegetative period is mixed with 5 * 10 4individual/mL concentration, every hole 100 μ L are inoculated in 96 orifice plates and cultivate 24h after cell is fully adherent, remove original nutrient solution, add the nutrient solution containing different concns medicine, every hole 100 μ L, separately establish control group, add the nutrient solution containing 0.1%DMSO, cultivate 72h for 37 ℃; Complete, every hole adds 37 ℃ of 5mg/mL MTT 10 μ L to continue to cultivate careful abandoning supernatant after 4h, add DMSO 150 μ L/ holes, vibrate 10 minutes with abundant dissolving crystallized thing, by microplate reader, at 570nm wavelength place, measure OD value, press formula and calculate medicine to the inhibiting rate of Proliferation of Tumor Cells In Vitro (Inhibition Rate, IR), then use SPSS computed in software half-inhibition concentration (IC 50).
Cell proliferation inhibition rate (%)=(1-dosing group OD value/control group OD value) * 100
Test result is as Table 2.
The IC of Table 2. compounds to the effect of HL60 human leukocyte growth-inhibiting 50value (μ M, the trypan blue method of exclusion)
Table 3. compounds are to the inhibiting IC of HeLa growth of human cervical carcinoma Hela 50value (μ M, mtt assay)
Table 4. compounds are to the inhibiting IC of BEL7402 hepatoma cell growth 50value (μ M, mtt assay)
The IC of Table 5. compounds to the effect of MCF-7 human breast cancer cell growth-inhibiting 50value (μ M, mtt assay)
Result shows, compound of the present invention shows significant proliferation inhibition activity for different knurl strains.

Claims (4)

1. tetrahydroisoquinolicompounds compounds, it is selected from:
2. compound as claimed 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.
3. a pharmaceutical composition, the compound that it comprises any one in claim 1-2 and pharmaceutical excipient.
4. the purposes of the compound of any one in the medicine for the preparation of inhibition tumor cell propagation in claim 1-2.
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