CN109293493A - With the inhibition active novel benzhydryl class compound of mycobacterium tuberculosis - Google Patents

With the inhibition active novel benzhydryl class compound of mycobacterium tuberculosis Download PDF

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CN109293493A
CN109293493A CN201811268731.9A CN201811268731A CN109293493A CN 109293493 A CN109293493 A CN 109293493A CN 201811268731 A CN201811268731 A CN 201811268731A CN 109293493 A CN109293493 A CN 109293493A
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CN109293493B (en
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刘刚
吴杰
穆然
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Tsinghua University
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Abstract

The present invention relates to having to inhibit active novel benzhydryl analog derivative of mycobacterium tuberculosis and preparation method thereof, especially has and inhibit replicability and the active novel benzhydryl analog derivative of non-replicating mycobacterium tuberculosis and preparation method thereof.In particular it relates to formula (I) compound represented or its all possible isomers, prodrug, officinal salt, solvate or hydrate, wherein each variable is as used in the description.Further relate to the purposes of the preparation method, the pharmaceutical composition comprising the compounds of this invention and the compounds of this invention of the compounds of this invention in the drug that preparation Killing Mycobacterium Tuberculosis infects caused disease.

Description

With the inhibition active novel benzhydryl class compound of mycobacterium tuberculosis
Technical field
The present invention relates to having to inhibit active novel benzhydryl analog derivative of mycobacterium tuberculosis and preparation method thereof, Especially have and inhibits replicability and the active novel benzhydryl analog derivative of non-replicating mycobacterium tuberculosis and its preparation The drug of disease caused by method and the compound are infected with single or composition forms in preparation Killing Mycobacterium Tuberculosis In purposes.
Background technique
Tuberculosis (Tuberculosis, TB) be by mycobacterium tuberculosis (Mycobacterium Tuberculosis, Mtb the suffered from history longest of the mankind caused by) one of brings disaster to the most wide lethal communicable disease in face, still seriously affects the mankind so far Health.1993, the World Health Organization (WHO) announced " the global tuberculosis state of emergency ", and determined that annual March 24 is " World Tuberculosis Prevention and Cure Day ".1998, the World Health Organization reaffirmed to contain that the action of TB is very urgent again.Currently, the whole world is super The population for crossing 1/4 has infected Mtb, and at least 2,000,000 people die of TB every year.The drug resistance and latency of tuberculosis are treatment knots The significant challenge encountered when core disease.Statistics shows that the new cases of annual multi-drug resistant tuberculosis (MDR-TB) are 600,000, and feels The crowd's treatment for contaminating extensive drug resistant M (XDR-TB) is increasingly complex.Latent tuberculosis (Latent TB) is considered current Another long main cause for the treatment of cycle.Tubercle bacillus has replicability (replicatingMtb) and non-replicating tubercle bacillus Two kinds of (non replicatingMtb), current viewpoint think that the latter is the master of TB recurrence and treatment cycle up to 6-9 months Cause.Tuberculotherapy has the characteristics that medication cycle is long, types of medicines is more, and antituberculotic and other drugs are (such as treatment AIDS AIDs and other chronic syndrome drugs) the medicine that shares be also required to pay special attention to.
So far, treating main policies lungy is still chemotherapy.The anti-TB of a line clinically used Drug includes isoniazid, rifampin, pyrazinamide and ethambutol.It is clinically daily to the therapeutic scheme of drug susceptibility TB Four kinds drug therapy 2 months more than oral, then isoniazid and rifampicin treatment 4 months are taken orally daily.And MDR-TB refers to different Cigarette hydrazine and rifampin-resistance need then to extend to 2 years with Second line Drug drug combination, treatment cycle after infection, and cure rate is about 50%-70%.XDR-TB refer to not only in first-line drug isoniazid and rifampin-resistance, but also in Second line Drug extremely The anti-TB Drug-resistant of few a kind of fluoroquinolones and at least one injectable.Due to different patients drug resistance and Immunological tolerance is different, causes the death rate for treating XDR-TB very high.And treat the crowd of TB and AIDs concurrent infection then face Face bigger challenge, the reason is that the hypoimmunity of HIV patient, greatly reduces the effect of drug.Currently, about 50% AIDs dies of the co-infection of Mtb.
Mycobacterium tuberculosis is aerobic-type bacterium, and growth temperature is 37 DEG C, and the most suitable growth pH value is 6.8-7.2.When in bacterium PH value (intrabacterial pH, pHIB) it is lower than 5.5, the duplication of mycobacterium tuberculosis can be serious suppressed.However tuberculosis branch Bacillus can resist the acidic environment in host macrophage, keep its pHIBStable state is retained into not replicated state and persistently. Once obtaining the environment adapted to, such as immunocompromised host, the withholding mycobacterium tuberculosis will develop as replicability mycobacterium tuberculosis.
After organism infection mycobacterium tuberculosis, phagosome (phagosome) swallows mycobacterium tuberculosis.And it ties Core mycobacteria can generally be survived in relatively mild by inhibiting phagosome mature and phagosome and lysosome merge In pH (6.2) environment.But after specific immune system is activated, T- cell then releases gamma interferon (INF- γ), INF- γ and then promotion phagosome maturation, and further promotion phagosome and lysosome fusion are phagolysosome, bite lysosome On film with H+The related V-ATPase albumen of active transport makes the pH value in its film be reduced to 4.5-5.0, greatly strengthens phagocytosis Acidic environment in lysosome, leads to H+Have the tendency that consumingly spreading into Mtb, and then reduce the intracorporal pH value of Mtb, inhibits The replication activity of Mtb.In addition, being also construed to, a large amount of H+ can support and cooperate with other antibacterial mechanisms in macrophage, Such as H+ can also further activating activities nitrogen intermediate (RNI) and reactive oxygen intermediate (ROI), free fatty acid, ubiquitin derive Peptides and the activity of lysosomal hydrolase etc..
And Mtb, in order to fight and be resistant to this acidic environment, its own forms certain protection system to keep pHIBSurely State, and then be able to hide.It is now recognized that participating in the pH of MtbIBThe memebrane protein for mainly having outer layer of stable state effect (OmpATb), magnesium ion transporter (MgtC) and the serine protease etc. encoded by Rv3671c gene.
Agrimophol (Agrimophol) is China scientific worker isolated one from conventional Chinese medicine hairyvein agrinonia rhizome Kind there is the active phloroglucinol derivatives compound of significant expelling tenia, herb for stopping blooding, anti-inflammatory, rhizome can control dysentery；At present Still without agrimophol to the relevant report of mycobacterium tuberculosis inhibitory activity.
Present need exist for it is new can effectively treat treatment tuberculosis, especially for treating latent tuberculosis disease simultaneously Significantly shorten the compound for the treatment of cycle lungy.
Summary of the invention
The present invention relates to novel benzhydryl class compound to it in the related disease of preparation treatment infection due to Mycobacterium tuberculosis The drug of disease, especially prepares the drug for treating replicability and non-replicating infection due to Mycobacterium tuberculosis and its related disease In purposes, particularly, the novel benzhydryl class compound of one kind involved in the present invention and its pharmaceutically acceptable combination There is the active, higher of pH in preferable reduction bacterium to inhibit the active, preferable of M. tuberculosis growth for object, the compound The activity of MDR-TB and XDR-TB growth that people's hepatomicrosome stability, lesser cytotoxicity and inhibition are clinically separated etc. is excellent Point has good application prospect in infection due to Mycobacterium tuberculosis related disease.
In the first aspect of the present invention, the invention proposes a kind of compounds.According to an embodiment of the invention, being formula (I) Stereoisomer, tautomer, nitrogen oxides, the hydrate, solvation of compound shown in compound represented or formula (I) Object, metabolite, pharmaceutically acceptable salt or prodrug:
Each R1、R3、R5、R6、R10It is each independently hydrogen, amino, itrile group ,-ORa、C1-6Alkoxy, halogen, C1-6Alkyl, C3-6Naphthenic base, wherein each C1-6Alkoxy, C1-6Alkyl, C3-6Naphthenic base it is independently unsubstituted or independently by 1,2, 3,4 or 5-OH ,-NH2、-NO2,-CN, halogen, C1-6Alkyl, C1-6Alkoxy or C1-6Alkylamino replaces；
R2It independently is hydrogen, hydroxyl, amino, itrile group ,-C (=O)-Rb,-C (=O)-ORc,-C (=O)-NRc1Rc2、C2-6 Alkynyl, C2-6Alkenyl, C1-6Alkoxy, C1-6Alkylamino, halogen, C1-6Alkyl, C3-6Naphthenic base, C6-10Aryl, benzyl, 3-9 original Molecular heterocycle, 5-10 former molecular heteroaryl, Rd- CH=N-ORc, wherein each C2-6Alkynyl, C2-6Alkenyl, C1-6Alkoxy, C1-6Alkyl, C3-6Naphthenic base, C6-10Aryl, benzyl, 3-9 former molecular heterocycle or 5-10 atom group At heteroaryl it is independently unsubstituted or independently by 1,2,3,4 or 5 C1-6Alkyl, C1-6Alkoxy, nitro, amino, hydroxyl Base, itrile group or halogen replace；
Each R4、R7、R9、R11It is each independently hydrogen, hydroxyl, amino, itrile group, nitro ,-C (=O)-Rb,-C (=O)- ORc,-C (=O)-NRc1Rc2、C2-6Alkynyl, C2-6Alkenyl, C1-6Alkoxy, halogen, C1-6Alkyl, C3-6Naphthenic base, C6-10Aryl, Benzyl, 3-9 former molecular heterocycle, 5-10 former molecular heteroaryl；Wherein, each C2-6Alkynyl, C2-6Alkenyl, C1-6Alkoxy, C1-6Alkyl, C3-6Naphthenic base, C6-10Aryl, benzyl, 3-9 former molecular heterocycle, 5-10 atom group At heteroaryl it is independently unsubstituted or independently by 1,2,3,4 or 5 C1-6Alkyl, C1-6Alkoxy, nitro, amino, nitrile Base or halogen replace；
R8It independently is hydrogen ,-ORe, amino, itrile group, C1-6Alkoxy, C1-6Alkylamino, halogen, C1-6Alkyl, C3-6Cycloalkanes Base, C2-6Alkynyl, C2-6Alkenyl；
RaIt independently is hydrogen, C1-6Alkyl, C2-6Alkynyl, C2-6Alkenyl or-(C=O) C1-6Alkyl；
RbIt independently is H ,-OH ,-NH2、C1-6Alkyl, C1-6Alkoxy or C3-7Naphthenic base；
Each Rc、Rc1、Rc2、RdIt is separately H or C1-6Alkyl；
ReIt independently is hydrogen, C1-6Alkyl ,-C1-6Alkyl-NH-C (=O)-C1-6Alkyl, C1-6Halogenated alkyl,
-C1-6Alkyl-(5-6 unit's heteroaryl)-NH-C (=O)-C1-6Alkyl-(5-10 circle heterocyclic ring base)-；
Or R1With R2With together with the atom that they are respectively connected with or R2With R3With the atom one being respectively connected with them Rise or R3With R4With together with the atom that they are respectively connected with or R4With R5With together with the atom that they are respectively connected with or R6With R7With together with the atom that they are respectively connected with or R7With R8With together with the atom that they are respectively connected with or R8With R9 With together with the atom that they are respectively connected with or R9With R10With together with the atom that they are respectively connected with or R10With R11With with The atom that they are respectively connected with is together or R11With R1With together with the atom that they are respectively connected with, formed 4-8 circle heterocyclic ring base or C4-8Naphthenic base, wherein the 4-8 circle heterocyclic ring base or C4-8Naphthenic base it is unsubstituted or optionally by 1,2,3,4 or 5 oxo, C1-6Alkyl, C2-6Alkenyl, hydroxyl or halogen replace；
Or R5With R6With together with the atom that they are respectively connected with or R1With R6With the atom one being respectively connected with them Rise or R5With R10With together with the atom that they are respectively connected with or R1With R10With together with the atom that they are respectively connected with, shape At 6-8 circle heterocyclic ring base or C6-8Naphthenic base, wherein the 6-8 circle heterocyclic ring base or C6-8Naphthenic base it is unsubstituted or optionally by 1, 2,3,4 or 5 oxos, C1-6Alkyl, halogen or hydroxyl replace；
X independently is key, C1-6Alkyl, C1-6Alkoxy, amino, C1-6Alkylamino, C2-6Alkynyl, C2-6Alkenyl, Rf- C (= O)-Rg；
Each Rf、RgIt is each independently hydrogen, C1-6Alkyl, C1-6Halogenated alkyl, C1-6Hydroxy alkyl, C1-6Aminoalkyl.
According to an embodiment of the invention, above compound can further include following additional technical feature at least it One:
According to an embodiment of the invention, each R1、R3、R5、R6、R10It is each independently hydrogen, amino, itrile group ,-ORa、C1-3Alkane Oxygroup, halogen, C1-3Alkyl, C3-6Naphthenic base, wherein each C1-3Alkoxy, C1-3Alkyl, C3-6Naphthenic base independently not by Replace or independently by 1,2,3,4 or 5-OH ,-NH2、-NO2,-CN, halogen, C1-3Alkyl, C1-3Alkoxy or C1-3Alkylamino Replace；
R2It independently is hydrogen, hydroxyl, amino, itrile group ,-C (=O)-Rb,-C (=O)-ORc,-C (=O)-NRc1Rc2、C2-4 Alkynyl, C2-4Alkenyl, C1-3Alkoxy, halogen, C1-3Alkyl, C3-6Naphthenic base, phenyl, benzyl, 5-6 former molecular heterocycle Base, 5-6 former molecular heteroaryl, Rd- CH=N-ORc, wherein each C2-4Alkynyl, C2-4Alkenyl, C1-3Alkoxy, C1-3 Alkyl, C3-6The former molecular heterocycle of naphthenic base, phenyl, benzyl 5-6 or the 5-6 molecular heteroaryl of original are independently not It is substituted or independently by 1,2,3,4 or 5 C1-3Alkyl, C1-3Alkoxy, C1-3Alkylamino, nitro, amino, itrile group or halogen Replace；
Each R4、R7、R9、R11It is each independently hydrogen, hydroxyl, amino, itrile group, nitro ,-C (=O)-Rb,-C (=O)- ORc,-C (=O)-NRc1Rc2、C2-4Alkynyl, C2-4Alkenyl, C1-3Alkoxy, halogen, C1-3Alkyl, C3-6Naphthenic base, phenyl, benzyl, 5-6 former molecular heterocycle, 5-6 former molecular heteroaryl；Wherein, each C2-4Alkynyl, C2-4Alkenyl, C1-3Alkane Oxygroup, C1-3Alkyl, C3-6Naphthenic base, phenyl, benzyl 5-6 former molecular heterocycle or 5-6 former molecular heteroaryl It is independently unsubstituted or independently by 1,2,3,4 or 5 C1-3Alkyl, C1-3Alkoxy, nitro, amino, itrile group or halogen take Generation；
R8It independently is hydrogen ,-ORe, amino, itrile group, C1-3Alkoxy, C1-3Alkylamino, halogen, C1-3Alkyl, C3-6Cycloalkanes Base, C2-4Alkynyl, C2-4Alkenyl,；
RaIt independently is hydrogen, C1-3Alkyl, C2-4Alkynyl, C2-4Alkenyl or-(C=O) C1-3Alkyl；
RbIt independently is H ,-OH ,-NH2、C1-3Alkyl, C1-3Alkoxy or C3-6Naphthenic base；
Each Rc、Rc1、Rc2、RdIt is separately H or C1-3Alkyl；
ReIt independently is hydrogen, C1-3Alkyl ,-C1-3Alkyl-NH-C (=O)-C1-3Alkyl, C1-3Halogenated alkyl,
Or R1With R2With together with the atom that they are respectively connected with or R2With R3With the atom one being respectively connected with them Rise or R3With R4With together with the atom that they are respectively connected with or R4With R5With together with the atom that they are respectively connected with or R6With R7With together with the atom that they are respectively connected with or R7With R8With together with the atom that they are respectively connected with or R8With R9 With together with the atom that they are respectively connected with or R9With R10With together with the atom that they are respectively connected with or R10With R11With with The atom that they are respectively connected with is together or R11With R1With together with the atom that they are respectively connected with, formed 5-6 circle heterocyclic ring base or C5-6Naphthenic base, wherein the 5-6 circle heterocyclic ring base or C5-6Naphthenic base it is unsubstituted or optionally by 1,2,3,4 or 5 oxo, C1-3Alkyl, C2-4Alkenyl, hydroxyl or halogen replace；
Or R5With R6With together with the atom that they are respectively connected with or R1With R6With the atom one being respectively connected with them Rise or R5With R10With together with the atom that they are respectively connected with or R1With R10With together with the atom that they are respectively connected with, shape At 6-7 circle heterocyclic ring base or C6-7Naphthenic base, wherein the 6-7 circle heterocyclic ring base or C6-7Naphthenic base it is unsubstituted or optionally by 1, 2,3,4 or 5 oxos, C1-3Alkyl, halogen or hydroxyl replace；
X independently is key, C1-3Alkyl, C1-3Alkoxy, amino, C1-3Alkylamino, C2-4Alkynyl, C2-4Alkenyl, Rf- C (= O)-Rg；
Each Rf、RgIt is each independently hydrogen, C1-3Alkyl, C1-3Halogenated alkyl, C1-3Hydroxy alkyl.
According to an embodiment of the invention, it is formula (II) or (IIa) compound represented or formula (II) or (IIa) shownization Stereoisomer, tautomer, hydrate, solvate, prodrug, nitrogen oxides or the pharmaceutically acceptable salt of object are closed,
According to an embodiment of the invention, it is formula (III) or (IIIa) compound represented or formula (III) or (IIIa) institute Show stereoisomer, tautomer, hydrate, solvate, prodrug, the nitrogen oxides or pharmaceutically acceptable of compound Salt,
According to an embodiment of the invention, it is formula (IV), (IVa), (IVb) or (IVc) compound represented or formula (IV), (IVa), the stereoisomer of compound shown in (IVb) or (IVc), tautomer, hydrate, solvate, prodrug, nitrogen oxygen Compound or pharmaceutically acceptable salt,
Each R12,R13,R14,R15It is each independently hydrogen, C1-6Alkyl.
According to an embodiment of the invention, each R12,R13,R14,R15It is each independently hydrogen, methyl, ethyl, propyl.
According to an embodiment of the invention, it is compound shown in formula (V) or (Va) compound represented or formula (V) or (Va) Stereoisomer, tautomer, hydrate, solvate, prodrug, nitrogen oxides or pharmaceutically acceptable salt,
Each R12、R13、R14、R15It is each independently hydrogen, C1-6Alkyl；Y is-N- or-O-.
According to an embodiment of the invention, each R12、R13、R14、R15It is each independently hydrogen, methyl, ethyl, propyl.
According to an embodiment of the invention, it is formula (VI) or (VIa) or (VIb) or (VIc) compound represented or formula (VI) or it is the stereoisomer of compound shown in (VIa) or (VIb) or (VIc), tautomer, hydrate, solvate, preceding Medicine, nitrogen oxides or pharmaceutically acceptable salt,
RwIt independently is C2-4Alkynyl, C2-4Alkenyl or C1-3Alkyl, wherein each C2-4Alkynyl, C2-4Alkenyl or C1-3Alkyl is only It is on the spot unsubstituted or by 1,2,3,4 C1-3Alkyl, halogen, nitro ,-CN, OH replace；
Each R12、R13、R14、R15、R16、R17、R18、R19It is each independently hydrogen, C1-6Alkyl；Y is-N- or-O-.
According to an embodiment of the invention, each R12、R13、R14、R15、R16、R17、R18、R19It is each independently hydrogen, methyl, second Base, propyl, RwIt independently is vinyl.
According to an embodiment of the invention, it is different for the solid of compound shown in formula (VII) compound represented or formula (VII) Structure body, tautomer, hydrate, solvate, prodrug, nitrogen oxides or pharmaceutically acceptable salt,
Each R12、R13、R14、R15、R16、R17、R18、R19It is each independently hydrogen, C1-6Alkyl；Y is-N- or-O-.
According to an embodiment of the invention, each R12、R13、R14、R15、R16、R17、R18、R19It is each independently hydrogen, methyl, second Base, propyl.
According to an embodiment of the invention, it is change shown in formula (VIII) or (VIII-a) or (VIII-b) or (VIII-c) Close stereoisomer, the tautomerism of compound shown in object or formula (VIII) or (VIII-a) or (VIII-b) or (VIII-c) Body, hydrate, solvate, prodrug, nitrogen oxides or pharmaceutically acceptable salt,
Each R12、R13、R14、R15It is each independently hydrogen, C1-6Alkyl
Each RwIt independently is C2-4Alkynyl, C2-4Alkenyl or C1-3Alkyl, wherein each C2-4Alkynyl, C2-4Alkenyl or C1-3Alkyl It is independently unsubstituted or by 1,2,3,4 C1-3Alkyl, halogen, nitro ,-CN, OH replace；R16It independently is hydrogen, C1-6Alkyl.
According to an embodiment of the invention, each R12、R13、R14、R15It is each independently hydrogen, methyl, ethyl, propyl.
According to an embodiment of the invention, RwFor acrylic, R16For methyl, ethyl, propyl.
According to an embodiment of the invention, it is formula (X) or formula (X-a) or formula (X-b) or formula (X-c) or formula (X-d) or formula (X-e) chemical combination shown in compound represented or formula (X) or formula (X-a) or formula (X-b) or formula (X-c) or formula (X-d) or formula (X-e) Stereoisomer, tautomer, hydrate, solvate, prodrug, nitrogen oxides or the pharmaceutically acceptable salt of object,
Each R20、R21It is each independently hydrogen, C1-6Alkyl, C1-6Alkoxy, C3-6Naphthenic base, halogen；
Each Rb1、Rb2It is each independently H ,-OH ,-NH2、C1-6Alkoxy, C1-6Alkyl or C3-7Naphthenic base；
Each R12、R13、R14、R15It is each independently hydrogen, C1-6Alkyl.
According to embodiments of the present invention, each R20、R21Be each independently hydrogen, methyl, ethyl, propyl, methoxyl group, ethyoxyl, N-propyl, isopropoxy, hexamethylene, halogen.Each Rb1、Rb2It is each independently H ,-OH ,-NH2、C1-3Alkoxy, C1-3Alkyl or C3-6Naphthenic base；Each R12、R13、R14、R15It is each independently hydrogen, hydrogen, methyl, ethyl, propyl.
Or R20With R21With together with the atom that they are respectively connected with, 5-6 circle heterocyclic ring base or C are formed5-6Naphthenic base, wherein The 5-6 circle heterocyclic ring base or C5-6Naphthenic base is unsubstituted or optionally by 1,2,3,4 or 5 oxo, C1-3Alkyl, C2-4Alkenyl, Hydroxyl or halogen replace；
According to embodiments of the present invention, R20With R21With together with the atom that they are respectively connected with, hexamethylene is formed.
According to an embodiment of the invention, X is amino, C1-3Alkyl, C1-3Alkoxy, C1-6Alkylamino, Rf- C (=O)-Rg。
According to an embodiment of the invention, X is carbon atom.
According to an embodiment of the invention, R11It independently is hydrogen, halogen, C1-3Alkyl, C1-3Alkoxy ,-C (=O)-Rb、-C (=O)-ORc, heterocycle that phenyl, benzyl, 5-6 atom are formed, 5-6 atom formation heteroaryl；Wherein, described each C1-3Alkyl, C1-3The heteroaryl difference that the heterocycle or 5-6 atom that alkoxy, phenyl, benzyl, 5-6 atom are formed are formed It is independently unsubstituted or independently by 1,2,3,4 or 5 C1-3Alkyl, C1-3Alkoxy, nitro, amino, itrile group or halogen take Generation.
According to an embodiment of the invention, R11For hydrogen.
According to an embodiment of the invention, R2It independently is hydrogen, hydroxyl, amino, itrile group ,-C (=O)-Rb,-C (=O)-ORc、 C2-4Alkynyl, C2-4Alkenyl, C1-3Alkoxy, halogen, C1-3Alkyl, C5-6Naphthenic base, phenyl, benzyl, 5-6 atom form miscellaneous Ring group, Rd- CH=N-ORc；Wherein, each C2-4Alkynyl, C2-4Alkenyl, C1-3Alkoxy, C1-3Alkyl, C5-6Naphthenic base, phenyl, The heterocycle that benzyl or 5-6 atom are formed is independently unsubstituted or independently by 1,2,3,4 or 5 C1-3Alkyl, C1-3Alkane Oxygroup, nitro, amino, itrile group or halogen replace；
Each Rc、RdIt is separately H or C1-3Alkyl；
Each RbIt independently is H ,-OH ,-NH2、C1-3Alkyl or C3-6Naphthenic base.
According to an embodiment of the invention, R2For hydrogen, chlorine, bromine,Cyano.
According to an embodiment of the invention, each R1、R3、R5、R6、R8、R10Be each independently is hydroxyl, hydrogen, methyl, methoxy Base, isopropoxy, butoxy, acetoxyl group, propenyloxy group, 3- chloropropanol oxygen radical, 3- acetamide propoxyl group；
Each R4Stand alone as hydrogen, chlorine, bromine, methyl, fluorine, cyano, carbonyl；
Each R8It independently is methoxyl group；
Each R7It independently is hydrogen, methyl, fluorine, chlorine, bromine, cyano, carbonyl；
Each R11It independently is hydrogen, methyl, phenyl, 4- fluorophenyl；
Each R2、R9It is each independently hydrogen, methyl, ethyl, propyl, hexyl, cyclopropyl, isobutyl group, 2- methyl-propyl；
Each R12、R13、R14、R15、R16、R17、R18、R19Being each independently is hydrogen, methyl, ethyl, propyl；
Or R9And R10It is connected as benzo isozole ring, wherein benzo isozole ring is independently by 1,2,3,4 or 5 H, C1-3 Alkyl；
Or R1And R2, R8And R9Close simultaneously is chromanone ring, wherein chromanone ring is independently by 1,2,3,4 or 5 H, C1-3 Alkyl；
Or R2And R3, R9And R10Close simultaneously is chromanone ring, wherein chromanone ring is independently by 1,2,3,4 or 5 H, C1-3 Alkyl；
Or R2And R3It is connected as chromanone ring or 2,3- dihydro-quinolinone ring, wherein chromanone ring or 2,3- dihydro-quinolinone Ring is independently by 1,2,3,4 or 5 H, C1-3Alkyl；
Or R8And R9It is connected as chromanone ring；
Or R1And R2It is connected as chroman ring or chromanone ring or 2,3- dihydro-quinolinone ring, wherein chroman ring or chromanone ring Or 2,3- dihydro-quinolinone ring is independently by 1,2,3,4 or 5 H, C1-3Alkyl；
Or R9And R10It is connected as chroman ring or chromanone ring；
Or R1And R2Be connected as benzo five-membered lactonic ring, wherein benzo five-membered lactonic ring independently by 1,2,3,4 or 5 H, C1-3Alkyl, C2-4Alkenyl, C2-4Alkynyl；
Or R5And R6It is connected as seven yuan of ether rings；
Or R8And R9Closing is chromanone ring, wherein chromanone ring is independently by 1,2,3,4 or 5 H, C1-3Alkyl；
Or R9And R10Closing is chromanone ring, wherein chromanone ring is independently by 1,2,3,4 or 5 H, C1-3Alkyl；
Or R2And R3It is connected as coumarin ring, wherein coumarin ring is independently by 1,2,3,4 or 5 H, C1-3Alkyl, C5-6 Naphthenic base, halogen replace；
Or R8And R9Closing is chromanone ring, wherein chromanone ring is independently by 1,2,3,4 or 5 H, C1-3Alkyl；
Or R9And R10Closing is chromanone ring, wherein chromanone ring is independently by 1,2,3,4 or 5 H, C1-3Alkyl.
According to an embodiment of the invention, its have it is one of following shown in structure or its stereoisomer, tautomer, Nitrogen oxides, hydrate, solvate, metabolite, pharmaceutically acceptable salt or prodrug,
In the second aspect of the present invention, the invention proposes a kind of pharmaceutical compositions.According to an embodiment of the invention, described Pharmaceutical composition includes mentioned-above compound.Inventors have found that mentioned-above compound has preferable reduce in bacterium Active, preferable people's hepatomicrosome stability of active, the higher inhibition M. tuberculosis growth of pH, lesser cell toxicant Property and the advantages that the higher activity for inhibiting the MDR-TB that is clinically separated and XDR-TB growth, and then include mentioned-above chemical combination The pharmaceutical composition of object can be treated effectively and prevention infection due to Mycobacterium tuberculosis related disease, especially replicability and non-replicating Infection due to Mycobacterium tuberculosis and its related disease.
According to an embodiment of the invention, described pharmaceutical composition further include pharmaceutically acceptable auxiliary material, excipient, Carrier, solvent or their combination.
According to an embodiment of the invention, described pharmaceutical composition further includes other therapeutic agents, the other therapeutic agents Selected from antituberculotic, inverase, the drug for treating diabetes.
According to an embodiment of the invention, the antituberculotic is isoniazid, rifampin, ethambutol or pyrazinamide.
According to an embodiment of the invention, the inverase is Sustiva or nevirapine.
In the third aspect of the present invention, the invention proposes mentioned-above compound or mentioned-above pharmaceutical compositions Purposes in medicine preparation.The drug is for preventing and/or treating children's tuberculosis, pulmonary tuberculosis, intestinal tuberculosis, scrofula, Bone tuberculosis, nephrophthisis, tubercular peritonitis, tubercular meningitis, drug susceptibility tuberculosis, multidrug resistance tuberculosis, extensively General drug-resistant tuberculosis, latent tuberculosis disease, the tuberculosis of HIV concurrent infection or disease relevant to mycobacterium tuberculosis infection.
In another aspect of this invention, the invention proposes the solids of compound shown in compound shown in formula (I) or formula (I) Isomers, tautomer, nitrogen oxides, hydrate, solvate, metabolite, pharmaceutically acceptable salt or prodrug The method of preparation, separation and purifying.
Content noted earlier only outlines certain aspects of the invention, but is not limited to these aspects.These aspect and its The content of his aspect will make more specific complete description below.
Detailed description of the invention
Fig. 1 is HepG2 cellulotoxic experiment evaluation result figure according to an embodiment of the present invention, wherein (A) agrimophol is implemented Example compound 122 and 128 reduces the dose curve of pH in BCG bacterium, wherein the EC of agrimophol50Value is 0.9669 μM, embodiment Close the EC of object 12250Value is 0.06502 μM, the EC of embodiment compound 12850Value is 0.0618 μM, 122 He of embodiment compound 128 compared to agrimophol, EC50Value improves 1 order of magnitude, and (B) agrimophol, embodiment compound 122 and 128 is in various concentration The lower dose curve for inhibiting the growth of HepG2 cell；The wherein IC of agrimophol50Value is 3.383 μM, embodiment compound 122 IC50Value is 15.69 μM, the IC of embodiment compound 12850Value is 4.375 μM；
Fig. 2 is that external Mtb according to an embodiment of the present invention and the MDR-Mtb and XDR-Mtb that are clinically separated existence activity are commented Valence figure, wherein (A) agrimophol, embodiment compound 122 and 128 inhibit Mtb existence activity rating in vitro；Wherein embodiment Closing object 122 can make CFU reduce by 1.5 orders of magnitude at 0.78 μM, and 3.125 μM can make CFU reduce by 3 orders of magnitude；Agrimophol CFU can be made to reduce by 1 order of magnitude at 3.125 μM with embodiment compound 128；Embodiment compound 122 inhibits Mtb raw in vitro The long acting raising for having 1 order of magnitude compared to agrimophol, (B) agrimophol, embodiment compound 122 and 128 inhibit in vitro MDR-Mtb existence activity rating；Wherein embodiment compound 122 and agrimophol inhibit the MIC of MDR-Mtb growth90Value is 1.56 μ M, the MIC of embodiment compound 12890Value is 12.5 μM, and (C) agrimophol, embodiment compound 122 and 128 inhibit XDR- in vitro Mtb existence activity rating；Wherein embodiment compound 122 and agrimophol inhibit the MIC of XDR-Mtb growth90Value is 6.25 μM, real Apply the MIC of a compound 12890Value is > 12.5 μM.
Specific embodiment
Detailed description of the invention book
Definition and general terms
The present invention will list in detail document corresponding to the content determining materialization, and embodiment is all accompanied by structure The diagram of formula and chemical formula.The present invention, which has, expectedly covers all choices, variant and coordinate, these may be as right Existing invention field is included in defined in it is required that like that.Those skilled in the art will identify it is many similar or equivalent to This described method and substance, these can be applied to the practice of the present invention.The present invention is limited to absolutely not method and substance Description.There are many documents and similar substance to distinguish or contradict with the present patent application including but not limited to term Definition, the usage of term, the technology of description, or the range controlled as the present patent application.
The present invention will be using defined below unless other aspects show.Purpose according to the present invention, chemical element is according to member Plain periodic table, CAS version and chemicals handbook, 75,thEd, 1994 define.In addition, organic chemistry General Principle is shown in " Organic Chemistry,"Thomas Sorrell,University Science Books,Sausalito:1999, and"March's Advanced Organic Chemistry,"by Michael B.Smith and Jerry March, John wiley & sons, NewYork:2007, therefore all contents have all merged bibliography.
As described in the invention, the compound of the present invention can be optionally replaced one or more substituent groups, such as General formula compound above, or as example special inside embodiment, subclass, and a kind of compound that the present invention is included. In general, term " substituted ", indicates one or more hydrogen atoms in given structure replaced specific substituent group.Unless Other aspects show that an optional substituent group can have a substituent group to be taken at various substitutable position of that group Generation.When in given structural formula more than one position can by selected from specific group one or more substituent groups replaced, that Substituent group can replace at various locations identical or differently.Wherein the substituent group can be, but be not limited to deuterium, F, Cl、Br、OH、C1-6Alkyl, C1-6Replaced the substituent group of alkoxy.
It is disclosed in the substituent group of each section of this specification, disclosed compound of present invention according to radical species or range.It is special It does not point out, the present invention includes each independent sub-combinations thereof of each member of these radical species and range.For example, term “C1-6Alkyl " refers in particular to the methyl being individually disclosed, ethyl, C3Alkyl, C4Alkyl, C5Alkyl and C6Alkyl.
Terminology used in the present invention " alkyl " includes the univalence hydrocarbyl of 1-6 carbon atom saturated straight chain or branch, wherein alkane Base can be individually optionally replaced one or more substituent groups described in the invention.Some of embodiments are alkyl Group contains 1-6 carbon atom, and other embodiment is that alkyl group contains 1-4 carbon atom, other embodiment It is that alkyl group contains 1-3 carbon atom.The further example of alkyl group includes, but is not limited to, methyl (Me ,- CH3), ethyl (Et ,-CH2CH3), n-propyl (n-Pr ,-CH2CH2CH3), isopropyl (i-Pr ,-CH (CH3)2), normal-butyl (n- Bu ,-CH2CH2CH2CH3), 2- methyl-propyl or isobutyl group (i-Bu ,-CH2CH(CH3)2), 1- methyl-propyl or sec-butyl (s- Bu ,-CH (CH3)CH2CH3), tert-butyl (t-Bu ,-C (CH3)3), n-pentyl (- CH2CH2CH2CH2CH3), 2- amyl (- CH (CH3) CH2CH2CH3), 3- amyl (- CH (CH2CH3)2), 2- methyl -2- butyl (- C (CH3)2CH2CH3), 3- methyl -2- butyl (- CH (CH3)CH(CH3)2), 3- methyl-1-butyl (- CH2CH2CH(CH3)2), 2-methyl-1-butene base (- CH2CH(CH3)CH2CH3), just Hexyl (- CH2CH2CH2CH2CH2CH3), 2- hexyl (- CH (CH3)CH2CH2CH2CH3), 3- hexyl (- CH (CH2CH3) (CH2CH2CH3)), 2- methyl -2- amyl (- C (CH3)2CH2CH2CH3), 3- methyl -2- amyl (- CH (CH3)CH(CH3) CH2CH3), 4- methyl -2- amyl (- CH (CH3)CH2CH(CH3)2), 3- methyl -3- amyl (- C (CH3)(CH2CH3)2), 2- first Base -3- amyl (- CH (CH2CH3)CH(CH3)2), 2,3- dimethyl -2- butyl (- C (CH3)2CH(CH3)2), 3,3- dimethyl -2- Butyl (- CH (CH3)C(CH3)3) etc..
Term " alkenyl " indicates that the monovalent hydrocarbon of 2-6 carbon atom straight chain or branch, wherein at least one C-C are sp2 Double bond, wherein the group of alkenyl can individually optionally replaced one or more substituent groups described in the invention, including The group for thering is negation, " suitable " or " E ", " Z " to define, wherein specific example includes, but is not limited to, vinyl (- CH= CH2), allyl (- CH2CH=CH2), etc..
Term " alkoxy " indicates that alkyl group is connected by oxygen atom with molecule rest part, and wherein alkyl group has Meaning as described in the present invention.In some embodiments, alkoxy base contains 1-6 carbon atom；In other embodiment party In case, alkoxy base contains 1-4 carbon atom；In other embodiment, alkoxy base contains 1-3 carbon atom. Replaced the substituent group that the alkoxy base can be described optionally by one or more present invention.
The example of alkoxy base includes, but is not limited to, methoxyl group (MeO ,-OCH3), ethyoxyl (EtO ,- OCH2CH3), 1- propoxyl group (n-PrO, n- propoxyl group ,-OCH2CH2CH3), 2- propoxyl group (i-PrO, i- propoxyl group ,-OCH (CH3)2), 1- butoxy (n-BuO, n- butoxy ,-OCH2CH2CH2CH3), 2- methyl-l- propoxyl group (i-BuO, i- fourth oxygen Base ,-OCH2CH(CH3)2), 2- butoxy (s-BuO, s- butoxy ,-OCH (CH3)CH2CH3), 2- methyl -2- propoxyl group (t- BuO, t- butoxy ,-OC (CH3)3), 1- amoxy (n- amoxy ,-OCH2CH2CH2CH2CH3), 2- amoxy (- OCH (CH3) CH2CH2CH3), 3- amoxy (- OCH (CH2CH3)2), 2- methyl -2- butoxy (- OC (CH3)2CH2CH3), 3- methyl -2- fourth Oxygroup (- OCH (CH3)CH(CH3)2), 3- methyl-l- butoxy (- OCH2CH2CH(CH3)2), 2- methyl-l- butoxy (- OCH2CH(CH3)CH2CH3), etc..
Term " alkyl amino " and " alkylamino " can be exchanged with each other use comprising " N- alkylamino " and " N, N- dioxane Amino ", wherein the hydrogen atom in amino group is separately replaced one or two alkyl group.Wherein, Yi Xieshi The scheme of applying is that alkylamino is one or two C1-12Alkyl is connected to the alkylamino group of the lower level formed on nitrogen-atoms. In other embodiments, alkylamino is one or two C1-6Alkyl is connected to the alkyl of the lower level formed on nitrogen-atoms Amino group.In other embodiments, alkylamino is one or two C1-4Alkyl be connected to formed on nitrogen-atoms it is lower The alkylamino group of grade.Also in other embodiments, alkylamino is one or two C1-3Alkyl is connected to nitrogen-atoms The alkylamino group of the lower level of upper formation.Suitable alkylamino radicals can be alkyl monosubstituted amino or dialkyl amido, alkane The example of amino includes, but is not limited to, N- methylamino, N- ethylamino, N, N- dimethylamino, N, N- lignocaine etc..
Term " alkynyl " indicates that the monovalent hydrocarbon containing 2-6 carbon atom straight chain or branch, wherein at least one C-C are Tri- key of sp, wherein alkynyl group can individually optionally replaced one or more substituent groups described in the invention, wherein Some embodiments are that alkyl group contains 2-6 carbon atom, and other embodiment is that it is former that alkyl group contains 2-4 carbon Son.Specific example includes, but is not limited to, acetenyl (- C ≡ CH), propargyl (- CH2C ≡ CH), propinyl (- C ≡ C- CH3), alkynes butyl (- CH2CH2C≡CH、-CH2C≡CCH3、-C≡CCH2CH3With-CH (CH3) C ≡ CH) and alkynes amyl (- CH2CH2CH2C≡CH、-CH2CH2C≡CCH3、-CH2C≡CCH2CH3、-C≡CCH2CH2CH3、-CH2CH(CH3)C≡CH、-CH (CH3)CH2C≡CH、-C(CH3)2C≡CH、-CH(CH3)C≡CCH3With-C ≡ CCH (CH3)2) etc..
Term " naphthenic base " indicates containing 3-9 carbon atom, monovalent or multivalence saturation monocycle, bicyclic or three ring bodies System.In one embodiment, naphthenic base includes 3-9 carbon atom；In another embodiment, naphthenic base includes that 3-8 carbon is former Son；In another embodiment, naphthenic base includes 3-7 carbon atom；In other embodiment, naphthenic base includes 3-6 Carbon atom.The group of naphthene base can be independently unsubstituted or be taken by one or more substituent groups described in the invention Generation.
Term " n former molecular ", wherein n is integer, the number of ring member nitrogen atoms in molecule is typically described, described The number of ring member nitrogen atoms is n in molecule.For example, piperidyl is the heterocycle of 6 annular atoms composition.
Term " heterocycle " refers to comprising 3-9 annular atom, non-aromatic, and saturation or part are unsaturated, unit price Or the monocyclic, bicyclic or tricyclic system of multivalence, wherein at least one annular atom are selected from nitrogen, sulphur or oxygen atom.Wherein, the heterocycle Replaced the substituent group that base group can be described optionally by one or more present invention.Unless otherwise stated, heterocycle can be with It is carbon-based or nitrogen base, and-CH2Group can be substituted optionally by-C (=O)-or-C (=S)-.The sulphur atom of ring can be optional Ground is oxidized to S- oxide.The nitrogen-atoms of ring can optionally be oxidized to N- oxide.In some embodiments, heterocycle Base is the heterocycle of 3-9 annular atom composition.In some embodiments, heterocycle is the heterocycle of 5-9 annular atom composition. In some embodiments, heterocycle is the heterocycle of 3-6 annular atom composition.In some embodiments, heterocycle 4-6 The heterocycle of a annular atom composition.In some embodiments, heterocycle is the heterocycle of 5-6 annular atom composition.Another In a little embodiments, heterocycle is the heterocycle of 4 annular atoms composition.In other embodiments, heterocycle is 5 ring originals Molecular heterocycle.Also in some embodiments, heterocycle is the heterocycle of 6 annular atoms composition.
The example of " heterocycle " includes, but is not limited to, pyrrolidinyl, tetrahydrofuran base, dihydrofuryl, thiophane Base, THP trtrahydropyranyl, dihydro pyranyl, tetrahydro thiapyran base, piperidyl, morpholinyl, thio-morpholinyl, thiophene oxane base, piperazinyl Deng.
Term " hetero atom " indicates one or more O, S, N, P and Si, the form including any oxidation state of N, S and P；The primary, The form of secondary, tertiary amine and quaternary ammonium salt；Or the substituted form of hydrogen in heterocycle on nitrogen-atoms, for example, N is (as 3,4- dihydro- N in 2H- pyrrole radicals), NH (as the NH in pyrrolidinyl) or NR (NR in pyrrolidinyl replaced as N-).
Term " halogen " or " halogen atom " refer to F, Cl, Br or I.
Term " aryl " indicates the monocycle containing 6-10 annular atom or 6-9 annular atom or 6-8 annular atom, bicyclic With the carbocyclic ring system of tricyclic, wherein at least one ring system be it is aromatic, wherein each ring system include 3-7 atom The ring of composition, and there are one or more tie points to be connected with the rest part of molecule.The example of term aryl group may include Phenyl, naphthalene and anthryl.The aryl group can be individually optionally by one or more substituent group institutes described in the invention Replace.
Term " heteroaryl " is indicated containing 5-10 annular atom or 5-8 annular atom or 9-10 annular atom or 9 rings The monocycle of atom or 5-6 annular atom, bicyclic and three-ring system, wherein at least one ring is aromatic rings, and at least one virtue Fragrant ring includes one or more hetero atoms, and wherein each ring system includes the ring of 5-7 annular atom composition, and has one or more A tie point is connected with molecule rest part.In some embodiments, heteroaryl be comprising 1,2,3 or 4 be independently selected from nitrogen, The heteroaryl of the heteroatomic 5-10 annular atom of sulphur and oxygen composition.In other implementation cases, heteroaryl be comprising 1,2,3 or The heteroaryl that 4 heteroatomic 5-9 annular atoms for being independently selected from nitrogen, sulphur and oxygen form.In other implementation cases, heteroaryl To be independently selected from the heteroaryl that the heteroatomic 9-10 annular atom of nitrogen, sulphur and oxygen forms comprising 1,2,3 or 4.At other In implementation case, heteroaryl is the heteroaryl that heteroatomic 9 annular atoms composition of nitrogen, sulphur and oxygen is independently selected from comprising 1,2,3 or 4 Base.In other embodiments, heteroaryl is a for the heteroatomic 5-6 for being independently selected from nitrogen, sulphur and oxygen comprising 1,2,3 or 4 The heteroaryl of annular atom composition.And the heteroaryl can be substituted or non-substituted, and wherein substituent group can be, but not It is limited to deuterium, F, Cl, Br, OH, C1-6Alkyl, C1-6Alkoxy.
Unless otherwise indicated, structural formula described in the invention includes that (such as mapping is different for all isomeric forms Structure, diastereo-isomerism and geometrical isomerism (or conformational isomerism): such as R, S configuration containing asymmetric center, (Z) of double bond, (E) isomers, and the conformer of (Z), (E).Therefore, the single three-dimensional chemical isomer of the compound of the present invention or its is right Reflect isomers, the mixture of diastereoisomer or geometric isomer (or conformer) belongs to the scope of the present invention.
Term " prodrug " used in the present invention represents a compound and is converted into formula (I) compound represented in vivo. Such conversion is hydrolyzed in blood by pro-drug or is that precursor structure is influenced through enzymatic conversion in blood or tissue.This hair Bright pro-drug compounds can be ester, and ester can be used as the phenyl ester class that has of pro-drug, aliphatic in existing invention (C1-24) esters, pivaloyloxymethyl esters, carbonic ester, carbamates and amino acid esters.Such as one in the present invention Compound includes hydroxyl, it can is acylated to obtain the compound of prodrug form.Other prodrug forms include Phosphate, if these phosphate compounds are obtaining through the di on parent.It is completely begged for about pro-drug By following documents can be referred to: T.Higuchi and V.Stella, Pro-drugs as Novel Delivery Systems,Vol.14of the A.C.S.Symposium Series,Edward B.Roche,ed.,Bioreversible Carriers in Drug Design,American Pharmaceutical Association and Pergamon Press,1987,J.Rautio et al,Prodrugs:Design and Clinical Applications,Nature Review Drug Discovery,2008,7,255-270,and S.J.Hecker et al,Prodrugs of Phosphates and Phosphonates, JournalofMedicinal Chemistry, 2008,51,2328-2345.
Unless otherwise indicated, all tautomeric forms of the compound of the present invention are included in the scope of the present invention Within.In addition, unless otherwise indicated, the structural formula of compound described in the invention includes one or more different originals The enriched isotope of son.
" metabolite " refers to specific compound or its salt product obtained by metabolic action in the body.One change The metabolite for closing object can be identified that activity can be retouched by such as the present invention by technology well-known in the art It adopts as stating and is experimentally characterized.Such product can be by passing through oxidation, reduction, water to drug compound Solution, amidated, deamidation, esterification, degreasing, the methods of enzymatic lysis etc. obtain.Correspondingly, the present invention includes compound Metabolite, including the compound of the present invention and mammal are come into full contact with into metabolite caused by a period of time.
The definition of neutral body chemistry of the present invention and the use of convention are typically referenced to following documents: S.P.Parker, Ed., McGraw-Hill Dictionary of Chemical Terms(1984)McGraw-Hill Book Company,New York；and Eliel,E.and Wilen,S.,"Stereochemistry of Organic Compounds",John Wiley&Sons, Inc., New York, 1994. the compound of the present invention may include asymmetric center or chiral centre, therefore There are different stereoisomers.All stereoisomeric forms in any ratio of the compound of the present invention, it is including but not limited to, diastereomeric Body, enantiomter, atropisomer and their mixture, such as racemic mixture constitute a part of the invention. Many organic compounds all exist with optical active forms, i.e. the plane of their capable Plane of rotation polarised lights.In description light When learning reactive compound, prefix D, L or R, S are used to indicate the absolute configuration at molecular chiral center.Prefix d, l or (+), (-) use Come name compound linearly polarized light rotate symbol, (-) or l refer to compound be it is left-handed, prefix (+) or d refer to chemical combination Object is dextrorotation.The chemical structure of these stereoisomers is identical, but their stereochemical structure is different.It is specific vertical Body isomers can be enantiomer, and the mixture of isomers is commonly referred to as enantiomeric mixture.The enantiomer of 50:50 mixes Object is referred to as racemic mixture or racemic modification, this, which may cause in chemical reaction process, does not have stereoselectivity or three-dimensional fixed Tropism.Term " racemic mixture " and " racemic modification " refer to the mixture of equimolar two enantiomters, lack light Learn activity.
Term " tautomer " or " tautomeric form " refer to that the isomer of the structure of different-energy can be with Pass through the mutual inversion of phases of low energy barrier.Such as proton tautomer (i.e. prototropic tautomer) includes passing through proton transfer Interconversion, such as the isomerization of keto-enol and imine-enamine.Valence (chemical valence) tautomer includes Recombinate the interconversion of bonding electrons.Unless otherwise noted, all tautomeric forms of the compounds of this invention are all of the invention Within the scope of.
" pharmaceutically acceptable salt " used in the present invention refers to the organic salt and inorganic salts of the compound of the present invention.Medicine Acceptable salt is known to us in fields on, such as document: S.M.Berge et al., describe pharmaceutically acceptable salts in detail in J.Pharmaceutical Sciences,66: 1-19,1977. documented.The salt that pharmaceutically acceptable nontoxic acid is formed includes, but is not limited to, anti-with amino group The inorganic acid salt that should be formed have hydrochloride, hydrobromate, phosphate, sulfate, perchlorate and acylate such as acetate, Oxalates, maleate, tartrate, citrate, succinate, malonate pass through described in the books or literature Other methods such as ion-exchanges obtains these salt.Other pharmaceutically acceptable salts include adipate, malate, 2- Hydracrylate, alginates, ascorbate, aspartate, benzene sulfonate, benzoate, bisulphate, borate, fourth Hydrochlorate, camphor hydrochlorate, camsilate, cyclopentyl propionate, digluconate, lauryl sulfate, esilate, first Hydrochlorate, fumarate, gluceptate, glycerophosphate, gluconate, Hemisulphate, enanthate, caproate, hydrogen Iodate, 2- hydroxy-ethanesulfonate salt, lactobionate, lactate, laruate, lauryl sulfate, malate, the third two Hydrochlorate, mesylate, 2- naphthalene sulfonate, nicotinate, nitrate, oleate, palmitate, pamoate, pectate, persulfuric acid Salt, 3- phenylpropionic acid salt, picrate, pivalate, propionate, stearate, rhodanate, tosilate, 11 Hydrochlorate, valerate, etc..Salt obtained by an appropriate base includes alkali metal, alkaline-earth metal, ammonium and N+(C1-4Alkyl)4Salt. The compound that the present invention is also intended to contemplate the group of any included N is formed by quaternary ammonium salt.Water-soluble or oil-soluble or dispersion Product can be obtained by quaternization.Alkali or alkaline earth metal salt includes sodium, lithium, potassium, calcium, magnesium, etc..Pharmaceutically may be used The salt of receiving further comprises appropriate, nontoxic ammonium, the amine cation that quaternary ammonium salt and gegenions are formed, as halide, Hydroxide, carboxylate, hydrosulphate, phosphoric acid compound, nitric acid compound, C1-8Sulphonic acid compound and aromatic sulphonic acid compound.
" solvate " of the invention refers to that one or more solvent molecules and the compound of the present invention are formed by association Object.The solvent for forming solvate includes, but is not limited to, water, isopropanol, ethyl alcohol, methanol, dimethyl sulfoxide, ethyl acetate, second Acid, ethylaminoethanol.Term " hydrate " refers to that solvent molecule is that water is formed by associated matter.
In the present invention, when being had in structural formulaOr when simileys, refer to that the covalent bond is in paper The position of either above or below, it is however noted that, if not illustrating, this configuration only has opposite meaning.Together Sample, if not illustrating, is also only the relative position of group when referring to " suitable " or negation.
Formula (I) compound can by it is other it is protected in the form of or derivative in the form of exist, these forms are to this field It is it will be apparent that being intended to be limited solely by the scope of the present invention for technical staff.
It treats the present invention relates to the compound and using the compound by the germ mammalian bacterial of tuberculosis Infectious diseases, specifically it is suitable for treatment tuberculosis as caused by tubercle bacillus affection.
The present invention includes the drug containing therapeutic dose the compounds of this invention and one or more pharmaceutically acceptable carriers And/or the pharmaceutical composition of excipient.Carrier includes such as salt water, buffered saline, glucose, water, glycerol, the knot of ethyl alcohol and they It closes, more fully hereinafter discusses.If desired, the composition can also be slow comprising small amount of wetting agent or emulsifier or pH Electuary.The composition can be liquid solution, suspension, emulsion, tablet, pill, capsule, extended release preparation or powder.It should Composition can be configured to suppository with traditional adhesive and carrier such as triglyceride.Oral preparation may include that standard carries The mannitol of body such as drug grade, lactose, starch, magnesium stearate, saccharin sodium, cellulose and magnesium carbonate, etc..Optionally make Depending on agent, preparation can be related to mixing, and pelletize and compress or solvent components.In another approach, the composition can be prepared At nano particle.
The pharmaceutical carrier used can be solid or liquid.
Carrier or excipient may include time delay material known in the art, such as glycerin monostearate or distearyl Acid glyceride may also include wax, ethyl cellulose, hydroxypropyl methyl cellulose, methylmethacrylate etc..When preparation is used for mouth When taking, it is recognized that in PHOSALPG-50 (phospholipid and 1,2-PD are concentrated, A.Nattermann&Cie.GmbH) 0.01% Tween 80 is used for the preparation of the acceptable oral preparation for other compounds, is adapted to variousization of the invention Close the preparation of object.
Miscellaneous medicament forms can be used when giving the compounds of this invention.If preparation can using solid carrier For tablet, the powder being placed into hard capsule or piller form or pastille or Lozenge forms.The amount of solid carrier is in very great Cheng Change on degree, it is preferred that from about 25mg to about 1g.If using liquid-carrier, preparation can be syrup, emulsion, soft capsule, Ampoule or bottle or aseptic injectable solution or suspension in non-aqueous liquid suspension.
Various release systems are administrations that is known and can be used for compound or its various preparation, these preparations include piece Agent, capsule, the solution of injectable, the capsule in liposome, particle, microcapsules, etc..The method of introducing includes but does not limit to It is intradermal in skin, intramuscular, intravenous in peritonaeum, subcutaneous, in nasal cavity, lung, peridural, the sum of eyes (generally preferable) oral route.Compound can be administered by any convenient or other approach appropriate, such as be passed through Injection or bolus injection, by epithelium or mucosal route (for example, oral mucosa, rectum and intestinal mucosa, etc.) absorb or logical It the bracket of overload drug and can be administered together with other biological activities agent.It can be administered either systemically or locally.For nose, branch When the treatment or prevention of tracheae or lung disease, preferred administration route is oral, nasal administration or bronchus smoke agent or sprayer.
General synthetic method
Generally, the compound of the present invention described method can be prepared through the invention, unless there are further Explanation, wherein the definition of substituent group is indicated before.Following reaction scheme and embodiment is for being further illustrated this hair Bright content.
Those skilled in the art will realize that: chemical reaction described in the invention can be used to suitably prepare perhaps Other compounds mostly of the invention, and other methods for the preparation of the compounds of the present invention are considered as in model of the invention Within enclosing.For example, the synthesis of the compound of those non-illustrations can be successfully by those skilled in the art according to the present invention It is completed by method of modifying, such as protection interference group appropriate, by utilizing other known reagent in addition to described in the invention , or reaction condition is made into some conventional modifications.In addition, reaction disclosed in this invention or known reaction condition are also generally acknowledged Ground is suitable for the preparation of other compounds of the invention.
The embodiments described below, unless other aspects show that all temperature are set to degree Celsius (DEG C).Used in experiment Reagent unless otherwise instructed, is purchased from Beijing coupling Science and Technology Ltd., Beijing lark prestige Science and Technology Ltd., Acros Organics, Alfa Aesar, Sigma-Aldrich and TCI, not purified direct use.Experiment solvent for use is mainly purchased from Beijing Chemical Plant and Xilong Chemical Co., Ltd, except THF and DMF is through VAC company of the U.S. (Vacuum atmospheres Company) solvent purification system is further processed outer, remaining unprocessed direct use.GF254Tlc silica gel plate, GF254Silica gel thickness prepares plate and column silica gel for chromatography powder (60-100 mesh, 160-200 mesh, 200-300 mesh) is purchased from Qing Daohai Foreignize factory.
HPLC-MS analyzer: HPLC analyzer is Agilent 1100HPLC system, and Agilent G1312A is pumped, Agilent G1314A UV detector, Agilent G1313A autosampler, Agilent G1316A column oven and shunting Valve.Chromatographic column is Kromasil C18 analytical column (4.6 μm, 4.6mm × 50mm), is purchased from DIKMA company.Mobile phase be containing The acetonitrile and water of 0.05%HCOOH.Linear gradient elution 5:95 (v:v) acetonitrile-H2O to 95:5 (v:v) acetonitrile-H2O, time 5minutes, flow velocity 1mL/min.UV Detection wavelength 254nm.ThermoFinnigan LCQ-
Advantage mass spectrograph, 5% in eluent is further separated into mass spectrograph, is scanned using cation or anion Mode, electric spray ion source (ESI).It is mainly used for the Preliminary Determination of reaction monitoring and compound purity.
UPLC-MS analyzer: the Acquity UPLC-MS system of Waters company, including binary solvent manager, sample Manager, chromatographic column manager, PDA detector and SQ mass detector.Chromatographic column is the Acquity of Waters companyBEH C18 column (1.7 μm, 2.1mm × 50mm).Mobile phase is acetonitrile and water containing 0.05%HCOOH.Linear gradient Elute 5:95 (v:v) acetonitrile-H2O to 95:5 (v:v) acetonitrile-H2O, time 3minutes, flow velocity 0.3mL/min.UV Detection wavelength 254nm.SQ mass spectrometer detector uses cation or anion scanning mode, electron spray ion Source (ESI).It is mainly used for the Preliminary Determination of reaction monitoring and compound purity.
HPLC analyzer: Agilent 1260HPLC system, Agilent G1311C quaternary pump, Agilent G4212B are purple External detector, Agilent G1367E high-performance autosampler, Agilent G1316A column oven.Chiral analysis column: AD-H, 250 × 4.6mm, 5 μM of DAICEL CHIRALPAK (Japanese Daicel company DAICEL production).Mobile phase is positive oneself Alkane/isopropanol, isocratic elution.UV Detection wavelength 254nm.It is mainly used for the optics degree analysis of target compound.
High-resolution mass spectrometer: Agilent LC/MSD TOF system.Chromatographic column: AgilentZORBAX SB-C18 (Rapidresolution,3.5μm,2.1×30mm).Mobile phase: MeOH:H2O=75:25 (v:v), contains 5mmol/L first Acid, isocratic elution.Time 5min, flow velocity 0.40mL/min.Mass Spectrometer Method uses cation scanning mode, electric spray ion source (ESI).It is mainly used for measuring the accurate molecular masses of target compound.
Nuclear Magnetic Resonance: Bruker Avance 400MHz, solvent CDCl3,DMSO-d6,Acetone-d6or Methanol-d4。
Melting point apparatus: the micro melting point apparatus of Yanaco, OptiMelt melting point apparatus do not correct.
The use of logogram word below is through the present invention:
DMF dimethylformamide
POCl3Phosphorus oxychloride
MOM methoxyl methyl
DMSO dimethyl sulfoxide
NH4Cl ammonium chloride
THF tetrahydrofuran
NaBH3CN sodium cyanoborohydride
AlCl3Aluminium chloride
HgCl2Mercury chloride
ZnCl2Zinc chloride
NH4Br ammonium bromide
Oxone peroxide list potassium sulfonate
F-TEDA-BF4Fluoro- 1,4- diazabicyclo [2.2.2] octane two (tetrafluoro boric acid) salt of 1- chloromethyl -4-
SO2Cl2Sulfonic acid chloride
CuCN cuprous cyanide
BF3·Et2O boron trifluoride ether
TBAF.3H2O 4-butyl ammonium fluoride trihydrate
PPh3Triphenylphosphine
The chloro- 5,6- dicyano -1,4- benzoquinones of DDQ 2,3- bis-
DIPEA N, N- diisopropyl ethyl amine
NBS N-bromosuccinimide
Bis- (2- oxo -3- oxazolidinyl) the secondary phosphoryl chloride phosphorus oxychlorides of BOPCl
AIBN azo-bis-isobutyl cyanide
AIVN azobisisoheptonitrile
The green fluorescent protein of pHGFP transfection pH sensitivity
BCG BCG vaccine
BCG-pHGFP transfects the BCG of the green fluorescent protein plasmid of pH sensitivity
H37Rv-pHGFP transfects the H of the green fluorescent protein plasmid of pH sensitivity37Rv bacterial strain
MOMCl chloromethyl methyl ether
TsCl paratoluensulfonyl chloride
DCM methylene chloride
NCS N-chlorosuccinimide
HOSU n-hydroxysuccinimide
TEA triethylamine
EDC.HCl, 1- (3- dimethylamino-propyl) -3- ethyl-carbodiimide hydrochloride
FBS fetal bovine serum
CFU Colony Forming Unit
MDR-TB multi-drug resistant tuberculosis
The extensive drug resistant M of XDR-TB
Synthetic method: where each substituent group has meaning as described in the present invention.
In some embodiments of the invention, the invention discloses the preparation method of compound shown in formula (I), this method packets Include following route:
Route 1: the synthetic route and condition of intermediate
Reaction condition:
(a) using phloroglucin as starting material, by Vilsmeier-Haack formylated (such as DMF and phosphorus oxychloride, Oxalyl chloride and DMF), solvent is non-protonic solvent (such as dioxane, ethyl acetate, THF), with the equivalent of molar ratio 1:1 It is reacted, reaction temperature is room temperature or heating, is preferably heated.
(b) benzoyl restores.Intermediate is reduced to methyl, preferably NaBH under conditions of reducing agent3CN, solvent are non- Protonic solvent (such as THF), adjusting reaction solution pH with Bronsted acid is 4-5.
(c) F-C is acylated.2,4,6- tri- is made from different substituted excess acetyl chlorides under Lewis acid catalysis in intermediate Hydroxy-3-methyl benzophenone (or benzaldehyde) class intermediate.The preferred AlCl of Lewis acid3；It is carried out with the equivalent of molar ratio 1:1.2 Reaction；Reaction temperature is to heat, preferably 50 DEG C.
(d) protection of phenolic hydroxyl group selectivity.The preferred MOM of protecting group, equivalent are required protection phenolic hydroxyl group number equivalent；Solvent It is typically chosen DMF, DMSO, acetone, preferably acetone；Alkali (such as sodium hydrogen, the carbon of protection phenolic hydroxyl group number equivalent needed for being added simultaneously Sour hydrogen sodium, sodium carbonate), preferred sodium carbonate；The preferred room temperature of reaction temperature, depending on the reaction time is according to specific response situation.
(e) protection of phenolic hydroxyl group.The preferred methyl of protecting group；The alkali and dimethyl suflfate of 2 times of equivalents is added, reaction temperature is Reflux, depending on answering the specific response situation of basis of time.
(f) removing of protecting group.Solvent is protonic solvent (such as alcohol, water), preferably methanol.Also need Bronsted acid for catalysis Agent, such as hydrochloric acid, sulfuric acid etc., acid are 2 times of equivalents；Reaction temperature is reflux, depending on the reaction time is according to specific response situation, Generally 2-3h.
(g) double formylateds of phloroglucin.The same a of condition, only formylation reagent is 2 times of equivalents.
(h) benzoyl restores.The preferred Zn/HgCl of reducing agent2, solvent is non-protonic solvent (such as dioxane)； Need to be added the acid catalysis of 0.5 times of equivalent, preferably concentrated hydrochloric acid simultaneously.
(i) activation of phenyl ring carbon.N, N, N' are generally used, N'- tetramethylmethane diamines is as 1.2 times of equivalents of activator； Solvent is non-protonic solvent, preferably methylene chloride；Reaction temperature is room temperature, and the reaction time is generally 0.5h.
(j) substitution of phenyl ring.When substituent group is bromine, condition NH4Br is bromine source, and Oxone is oxidant, and room temperature is anti- Answer 3hs；When substituent group is fluorine, condition F-TEDA-BF4For Fluorine source, reaction temperature is -45 DEG C -0 DEG C.When substituent group is When chlorine, condition SO2Cl2For chlorine source, 3h is reacted at room temperature；When substituent group is cyano, condition i) NH4Br,Oxone, rt；ii)CuCN,DMF,130℃.
Route 2: the synthetic route and condition of intermediate
Reaction condition:
(a) using phosphonoacetate and different substituted ketone as substrate, using hydrogen sodium as alkali, THF is solvent, and temperature is 0℃,5h。
(b) ester hydrolysis.The alkali of 2 times of amounts, preferably potassium hydroxide；Solvent is alcohol or THF, preferably methanol；80℃,20h.
(c) building of chromanone ring.Lewis acid catalysis, generally alchlor and BF3·Et2O, preferably BF3·Et2O； Reaction temperature is 50 DEG C -70 DEG C, preferably 70 DEG C；Time is 3h.
(d) F-C is acylated.Reaction condition is the same as the c in route 1, the preferred BF of Lewis acid3·Et2O。
(e) protection of phenolic hydroxyl group selectivity.Reaction condition is the same as the d in route 1.
(f) building of chromanone ring.Methyl source: paraformaldehyde, formalin, acetal, preferably paraformaldehyde；It needs Big excess base, preferably 10 times of equivalents, the preferred organic base diethylamine of alkali is added；Solvent is protonic solvent, preferred alcohol；Reflux； 3d。
(g) removing of protecting group.Reaction condition is the same as the f in route 1.
(h) hydroxyl oxime.Hydroxylamine hydrochloride；Sodium carbonate does alkali；Methanol is solvent；Room temperature；3h.
(i) reduction of carbonyl.Reducing agent is generally sodium cyanoborohydride, sodium borohydride, zinc powder etc., preferably zinc powder；Reaction It should carry out in acid condition, preferably concentrated hydrochloric acid is transferred to 2-3；Temperature is 0 DEG C-room temperature.Time is 5h.
(j) protection of phenolic hydroxyl group selectivity.Reaction condition is the same as e in route 1, the preferred Ts of protecting group.
(k) protection of phenolic hydroxyl group.Reaction condition is the same as e in route 1.
(l) removing of protecting group.Reaction condition is TBAF.3H2O, THF, room temperature, 5h.
(m) activation of phenyl ring carbon.Reaction condition is the same as i in route 1.
(n) building of isozole ring.Reaction condition is PPh3And DDQ is oxidant, methylene chloride is solvent, room temperature, 4h。
(o) reduction amination of aniline.Using different substituted ethyl acetoacetates as acylting agent；Reducing agent is typically chosen Sodium cyanoborohydride；Acid is catalyst, generally organic proton acid, preferably acetic acid；Aprotic solvent is solvent, preferably two chloroethenes Alkane；Room temperature, for 24 hours.
(p) building of 2,3- dihydro-quinolinone ring.It is obtained using the acetum of hydrobromic acid in hot conditions.Preferable temperature It is 140 DEG C, depending on the reaction time is according to specific response situation, usually 7h.
(q) substitution of phenyl ring.Reaction condition is the same as j in route 1.
(r) 1) acetic anhydride, sodium acetate flow back；2) aqueous sodium carbonate, reflux.
(s) NBS, tetrahydrofuran, room temperature, 1h.
Route 3: the synthetic route and condition of intermediate
Reaction condition:
(a) F-C is acylated.Reaction condition is the same as the c in route 1.
(b) protection of phenolic hydroxyl group.It selects acetyl group as protecting group, generally uses chloroacetic chloride or aceticanhydride as acetyl group Source, preferably aceticanhydride；Alkali selects common organic base, such as triethylamine, DIPEA, pyridine, preferably DIPEA.Methylene chloride or THF is solvent, room temperature 20h.
(c) benzyl bromo.The source of bromine can be NBS, amine bromide, bromine simple substance, preferably NBS；Radical initiator is BOPCl, AIBN, AIVN, preferably AIBN；Select carbon tetrachloride for solvent；40℃；4h.
(d) removing of protecting group.Solvent is typically chosen protonic solvent, such as methanol；Acid selection proton acid, preferably sulphur Acid；Temperature is room temperature to 50 DEG C, preferably 50 DEG C；3h.
(e) substitution of phenyl ring.Reaction condition is the same as j in route 1.
(f) building of benzhydryl.Condition is i) R4=H, RCHO, CH3COOH,rt；ii)R4=CH2N(CH3)2, ZnCl2, dioxane, reflux.
(g) building of benzo ether ring.Solvent is DMF, DMSO, acetone, ethyl acetate, dioxane.Alkali is sodium bicarbonate, Sodium carbonate, potassium carbonate, cesium carbonate.It is preferred that group is combined into acetone, cesium carbonate, 5h, room temperature.
Route 4: the synthetic route and condition of intermediate
Reaction condition:
(a) building of chromanone.Raw material selects phloroglucin and various substituted ethyl acetoacetates；Acid be Bronsted acid or Person's Lewis acid, preferably phosphorus oxychloride；Solvent is proton alcohol, such as methanol, ethyl alcohol.Temperature is room temperature to 85 DEG C, preferably 85 DEG C； 3h。
(b) F-C is acylated.Source of the acetic anhydride as acetyl group；Nitromethane is as solvent, raw material cumarin and nitro Methane, it is reacted with the equivalent of molar ratio 1:7；The preferred AlCl of Lewis acid3；Reaction temperature is to heat, preferably 110 DEG C； 1h。
(c) bromo of phenyl ring.Its condition is NBS, and solvent is methylene chloride, normal-temperature reaction.
Route 5: the synthetic route and condition of target compound
Reaction condition:
The building of benzhydryl.Condition is i) R16=H, R13CHO,CH3COOH,rt；ii)R16=CH2N(CH3)2,ZnCl2, Isosorbide-5-Nitrae-dioxane, reflux.
Two methods are generally used for the connection of two segments, method one: raw under the conditions of existing for the aldehyde and Bronsted acid At target product；But since the activity of two segment reaction sites is not identical, lead to have partial monosomy polymerization in reaction process By-product.Method two: using dimethylamine segment as leaving group come priming reaction site, it is high under Lewis acid catalysed conditions Feature of the present invention: the generation target product of yield using dimethylamine segment come priming reaction site, avoids the pair of monomer polymerization Product prepares target product by what Lewis acid catalysis was capable of high yield.
The embodiment of the present invention described in detail below.
1 1- of embodiment (3- (3- bytyry -2,6- dihydroxy -4- methoxyl group -5- methylbenzyl) -2,4,6- trihydroxy - 5- aminomethyl phenyl) -2- methyl butyl- 1- ketone
2,4,6- tri hydroxybenzaldehydes (1)
It measures DMF (15mmol) to set in a round bottom flask, POCl is slowly added dropwise under ice bath3(15mmol) drips off rear room temperature Stir 30min.By above-mentioned DMF and POCl under ice bath3Reaction solution be slowly added drop-wise to the 1,4- bis- of phloroglucin (15mmol) In six ring 6mL solution of oxygen, 2h is stirred at room temperature, stops reaction, reaction solution is poured into 100mL ice water, stands, wait precipitate crystal After filter, obtain orange red acicular crystal 11.867g, yield: 80.8%,1H-NMR(300MHz,DMSO-d6)δ11.46(s,2H), 10.65(s,1H),9.912(s,1H),5.78(s,2H)。
2,4,6- trihydroxytoluenes (2)
Intermediate 1 (10.04mmol) is dissolved in 200mLTHF, is added with stirring sodium cyanoborohydride (50mmol), reaction solution White is immediately become by orange red, is then turned yellow gradually, 2N HCl is added dropwise into reaction solution at this time, solution bleaches immediately again, with Gradual change is yellow again afterwards, then timely dropwise addition 2N HCl continues that 1h is stirred at room temperature, stop reaction, filter until reaction solution no longer turns yellow, It is concentrated under reduced pressure, extracts, be concentrated under reduced pressure, white solid 2 is obtained after silica gel column chromatography (petrol ether/ethyl acetate=5:1), yield: 68.3%,1H-NMR(300MHz,DMSO-d6)δ8.80(s,2H),8.67(s,1H),5.75(s,2H),1.79(s,3H)。
2,4,6- trihydroxy -3- methyl phenyl propyl ketones (3)
To addition AlCl in 1,2- dichloroethanes (6mL)3Butyl chloride is added under stirring at normal temperature in (14.96mmol) Intermediate 2 (6.8mmol) is added after 10min in (7.48mmol), 50 DEG C of reactions, stops reaction after 1h, cooling, is poured into containing ice In dilute hydrochloric acid, after stirring 5min, ethyl acetate extraction is concentrated under reduced pressure, and is obtained after silica gel column chromatography (DCM/MeOH=100:1) yellowish Color solid 3, yield: 85%,1H-NMR(300MHz,DMSO-d6)δ14.02(s,1H),10.49(s,1H),10.25(s,1H), 5.99 (s, 1H), 2.97 (t, J=7.2Hz, 2H), 1.83 (s, 3H), 1.54-1.66 (m, 2H), 0.91 (t, J=7.5Hz, 3H)。
2- hydroxy-3-methyl -4,6- dimethoxy methoxybenzene butanone (4)
Intermediate 3 (7.14mmol) is dissolved in 140mL acetone, and lower addition potassium carbonate (53.5mmol) is stirred at room temperature, stirring 2min is added MOMCl (17.85mmol), stops reaction, filtering, filtrate decompression concentration, silica gel column chromatography (petroleum ether/second after 1h Acetoacetic ester=30:1) after white solid 4, yield: 89%,1H-NMR(300MHz,DMSO-d6)δ13.68(s,1H),6.38 (s, 1H), 5.29 (s, 2H), 5.27 (s, 2H), 3.44 (s, 3H), 3.39 (s, 3H), 3.0 (t, J=7.2Hz, 2H), 1.94 (s, 3H), 1.59-1.66 (m, 2H), 0.92 (t, J=7.2Hz, 3H).
1- (2- methoxyl group -4,6- dimethoxy methoxyl group) -3- methyl phenyl propyl ketone (5)
At room temperature, into the acetone soln of intermediate 4 (5mmol), potassium carbonate (15mmol) is added in (20mL), stirs 2min, It is added dropwise dimethyl suflfate (15mmol), stirs 5min, be back to fully reacting, filter, filtrate decompression concentration, silica gel column chromatography Colorless oil 5 is obtained after (petrol ether/ethyl acetate=30:1), yield: 82%,1H-NMR(300MHz,DMSO-d6)δ6.67 (s, 1H), 5.21 (s, 2H), 5.13 (s, 2H), 3.60 (s, 3H), 3.39 (s, 3H), 3.34 (s, 3H), 2.67 (t, J= 7.2Hz, 2H), 2.02 (s, 3H), 1.51-1.66 (m, 2H), 0.89 (t, J=7.5Hz, 3H).
4,6- dihydroxy -2- methoxyl group -3- methyl phenyl propyl ketones (6)
At room temperature, into the methanol solution of intermediate 5 (3mmol), 0.5mL concentrated hydrochloric acid is added in (5mL), and flow back 1h, cooling, It is concentrated under reduced pressure, faint yellow solid 6 is obtained after silica gel column chromatography (petrol ether/ethyl acetate=20:1), yield: 93%,1H-NMR (300MHz,DMSO-d6) δ 12.30 (s, 1H), 10.35 (s, 1H), 6.15 (s, 1H), 3.65 (s, 3H), 2.92 (t, J= 7.2Hz, 2H), 1.94 (s, 3H), 1.53-1.63 (m, 2H), 0.89 (t, J=7.2Hz, 3H).
2,4,6- trihydroxy -3- methylbenzene (2- methyl) butanone (7)
Faint yellow solid 7 is obtained referring to the synthetic method of intermediate 3, yield: 83%,1H-NMR(300MHz,DMSO-d6)δ 14.10(s,1H),10.51(s,1H),10.27(s,1H),6.01(s,1H),3.75-3.84(m,1H),1.84(s,3H), 1.65-1.77 (m, 1H), 1.27-1.37 (m, 1H), 1.06 (d, J=6.3Hz, 3H), 0.84 (t, J=7.2Hz, 3H).
Intermediate 6 (0.1mmol), intermediate 7 (0.1mmol) are dissolved in 1mL acetic acid, and 10 drop formalins, room temperature is added 8h is stirred, 5mL ethyl acetate is added, is washed with saturated sodium bicarbonate aqueous solution to no longer bubbling, is extracted, is concentrated under reduced pressure, silica gel Column chromatographs (petrol ether/ethyl acetate=40:1) and obtains yellow solid powder, yield: 58-60 DEG C of 48%, mp,1H-NMR (300MHz,CDCl3)δ15.52(s,1H),9.58(s,1H),9.36(s,1H),3.83(s,2H),3.74-3.80(m,1H), 3.71 (s, 3H), 3.07 (t, J=7.2Hz, 2H), 2.10 (s, 3H), 2.08 (s, 3H), 1.80-1.92 (m, 1H), 1.67- 1.77 (m, 2H), 1.37-1.48 (m, 1H), 1.17 (d, J=7.2Hz, 3H), 0.99 (t, J=7.2Hz, 3H), 0.92 (t, J= 7.2Hz,3H).13C-NMR(150MHz,CDCl3):δ210.9,206.9,161.8,160.3,160.2,159.6,112.1, 109.5,107.8,105.9,103.5,101.8,61.5,45.8,44.3,26.9,18.2,16.7,16.2,13.9,12.0, 9.1,7.5.HRMS calcd for C25H33O8[M+H]+:461.21699；found:461.21753.
2 1- of embodiment (3- (3- bytyry -2,4,6- trihydroxy -5- methylbenzyl) -2,4- dihydroxy -6- methoxyl group - 5- aminomethyl phenyl) butyl- 1- ketone
Referring to the synthetic method of embodiment 1, title compound is obtained by intermediate 3 and intermediate 6, brown ceramic powder, yield: 77-79 DEG C of 35%, mp,1H-NMR(300MHz,CDCl3)δ15.51(s,1H),9.52(s,1H),9.31(s,1H),3.83(s, 2H), 3.71 (s, 3H), 3.07 (t, J=7.2Hz, 4H), 2.10 (s, 3H), 2.07 (s, 3H), 1.68-1.77 (m, 4H), 0.97-1.00(m,6H).HRMS calcd for C24H31O8[M+H]+:447.20134；found:447.20139.
3 3- of embodiment (3- bytyry -2,6- dihydroxy -4- methoxyl group -5- methylbenzyl) -2,4,6- trihydroxy -5- first Benzaldehyde
2,4,6- trihydroxy -3- tolyl aldehydes (8)
Faint yellow solid 8 is obtained referring to the synthetic method of intermediate 1, yield: 88%,1H-NMR(400MHz,DMSO-d6)δ 12.32(s,1H),10.63(s,1H),10.55(s,1H),9.92(s,1H),5.98(s,1H),1.82(s,3H)。
Referring to the synthetic method of embodiment 1, title compound is obtained by intermediate 8 and intermediate 6, faint yellow solid, is received Rate: 61%, mp > 210 DEG C,1H-NMR(400MHz,CDCl3)δ15.56(s,1H),13.78(s,1H),10.11(s,1H),9.72 (s, 1H), 9.06 (s, 1H), 3.80 (s, 2H), 3.72 (s, 3H), 3.08 (t, J=7.3Hz, 2H), 2.11 (s, 3H), 2.05 (s, 3H), 1.66-1.81 (m, 2H), 0.99 (t, J=7.4Hz, 3H)13C-NMR(100MHz,DMSO-d6)δ206.0, 192.2,162.5,160.4,159.4,159.1,158.9,158.0,110.5,110.0,108.3,105.4,105.3, 102.8,61.5,43.9,17.6,16.2,13.7,9.3,7.8.HRMS calcd for C21H25O8[M+H]+:405.15439； found:405.15408。
Embodiment 4 5,5 '-bis- (2,4,6- trihydroxy -3- tolyl aldehyde) methane
Referring to the synthetic method of embodiment 1, title compound is obtained by intermediate 8, faint yellow solid, yield: 24%, mp > 256 DEG C,1H-NMR(400MHz,DMSO-d6)δ11.29(s,2H),10.01(s,2H),3.71(s,2H),2.49(s,2H), 1.93(s,6H).13C NMR(100MHz,DMSO-d6)δ192.7,162.9,159.8,158.3,106.4,105.9,103.5, 16.5,8.5.HRMS calcd for C17H17O8[M+H]+:349.09179；found:349.09171.
5 1- of embodiment (3- (3- acetyl group -2,4,6- trihydroxy -5- methylbenzyl) -2,4- dihydroxy -6- methoxyl group - 5- aminomethyl phenyl) butane -1- ketone
2,4,6- trihydroxy -3- methyl acetophenones (9)
Faint yellow solid 9 is obtained referring to the synthetic method of intermediate 3, yield: 88%, yield: 83%,1H-NMR (400MHz,DMSO-d6)δ13.93(s,1H),10.50(s,1H),10.27(s,1H),5.99(s,1H),2.54(s,3H), 1.82(s,3H)。
Referring to the synthetic method of embodiment 1, title compound is obtained by intermediate 9 and intermediate 6, yellow solid, yield: 182-184 DEG C of 44%, mp,1H-NMR(400MHz,Acetone-d6)δ15.64(s,1H),10.47(s,1H),3.83(s, 2H), 3.79 (s, 3H), 3.16 (t, J=7.2Hz, 2H), 2.68 (s, 3H), 2.10 (s, 3H), 2.07 (s, 3H), 1.63-1.82 (m, 2H), 0.98 (t, J=7.4Hz, 3H)13C-NMR(150MHz,CDCl3)δ206.9,204.0,161.6,160.2, 159.6,159.5,112.1,109.5,107.8,105.6,104.2,101.8,61.5,44.3,32.6,18.2,16.1, 13.9,9.1,7.4.HRMS calcd for C22H27O8[M+H]+:419.17004；found:419.16995.
6 1- of embodiment (2,4- dihydroxy -6- methoxyl group -5- methyl -3- (2,4,6- trihydroxy -3- isobutyryl -5- first Base benzyl) phenyl) butane -1- ketone
2,4,6- trihydroxy -3- methylbenzene isobutyl ketones (10)
Faint yellow solid 10 is obtained referring to the synthetic method of intermediate 3, yield: 79%,1H-NMR(400MHz,DMSO-d6) δ14.03(s,1H),10.49(s,1H),10.24(s,1H),5.99(s,1H),3.85-3.95(m,2H),1.82(s,3H), 1.07(s,3H),1.05(s,3H)。
Referring to the synthetic method of embodiment 1, title compound is obtained by intermediate 10 and intermediate 6, yellow solid, is received Rate: 103-105 DEG C of 41%, mp,1H-NMR(400MHz,CDCl3)δ15.51(s,1H),9.55(s,1H),9.34(s,1H), 3.90-3.95 (m, 1H), 3.82 (s, 2H), 3.71 (s, 3H), 3.07 (t, J=7.3Hz, 2H), 2.10 (s, 3H), 2.08 (s, 3H), 1.68-1.78 (m, 2H), 1.18 (d, J=6.7Hz, 6H), 0.98 (t, J=7.3Hz, 3H)13C-NMR(100MHz, CDCl3)δ211.3,207.1,161.9,160.5,160.4,160.3,159.7,159.7,112.3,109.7,108.0, 106.0,103.3,102.1,61.7,44.4,39.3,34.2,19.4,18.4,16.3,14.1,9.3,7.6.HRMS calcd for C24H31O8[M+H]+:447.20134；found:447.2011.
7 1- of embodiment (3- (3- bytyry -2,6- dihydroxy -4- methoxyl group -5- methylbenzyl) -2,4,6- trihydroxy - 5- aminomethyl phenyl) -3- methybutane -1- ketone
2,4,6- trihydroxy -3- methylbenzene isoamyl ketone (11)
Yellow solid 11 is obtained referring to the synthetic method of intermediate 3, yield: 77%,1H-NMR(400MHz,Acetone- d6) δ 13.91 (s, 1H), 9.50 (s, 1H), 9.07 (s, 1H), 6.05 (s, 1H), 2.94 (d, J=6.7Hz, 2H), 2.14- 2.32(m,1H),1.96(s,3H),0.95(s,3H),0.93(s,3H)。
Referring to the synthetic method of embodiment 1, title compound is obtained by intermediate 11 and intermediate 6, yellow solid, is received Rate: 189-191 DEG C of 37%, mp,1H-NMR(400MHz,CDCl3)δ15.51(s,1H),9.52(s,1H),9.31(s,1H), 3.82 (s, 2H), 3.71 (s, 3H), 3.07 (t, J=7.3Hz, 2H), 2.97 (d, J=6.8Hz, 2H), 2.24-2.30 (m, 1H), 2.10 (s, 3H), 2.07 (s, 3H), 1.68-1.78 (m, 2H), 0.98 (t, J=7.3Hz, 3H), 0.97 (d, J= 7.3Hz,6H).13C-NMR(100MHz,CDCl3)δ207.1,206.6,161.9,160.5,160.3,160.1,159.7, 159.7,112.3,109.7,108.0,105.9,104.2,102.0,61.7,52.8,44.4,25.5,23.0,18.4,16.3, 14.1,9.3,7.6.HRMS calcd for C25H33O8[M+H]+:461.21699；found:461.21683.
8 1- of embodiment (3- (3- (cyclopropane carbonyl) -2,4,6- trihydroxy -5- methylbenzyl) -2,4- dihydroxy -6- first Oxygroup -5- aminomethyl phenyl) butane -1- ketone
2,4,6- trihydroxy -3- methylbenzene (2- cyclopropyl) ketones (12)
Yellow solid 11 is obtained referring to the synthetic method of intermediate 3, yield: 68%,1H-NMR(400MHz,Acetone- d6)δ13.79(s,1H),9.44(s,1H),9.04(s,1H),6.09(s,1H),3.29-3.62(m,1H),1.95(s,3H), 1.08-1.16(m,2H),0.93-0.96(m,2H)。
Referring to the synthetic method of embodiment 1, title compound is obtained by intermediate 12 and intermediate 6, yellow solid, is received Rate: 168-169 DEG C of 40%, mp,1H-NMR(400MHz,CDCl3)δ15.50(s,1H),15.22(s,1H),9.50(s,1H), 9.29 (s, 1H), 3.82 (s, 2H), 3.70 (s, 3H), 3.22-3.28 (m, 1H), 3.07 (t, J=7.3Hz, 2H), 2.10 (s, 3H), 2.09 (s, 3H), 1.69-1.78 (m, 2H), 1.29-1.33 (m, 2H), 1.02-1.07 (m, 2H), 0.99 (t, J= 7.3Hz,3H).13C-NMR(100MHz,CDCl3)δ207.0,205.3,161.9,160.4,160.3,159.7,159.2, 156.4,112.2,109.7,108.0,105.8,104.7,102.5,61.7,44.4,20.7,18.4,16.3,14.1,12.6, 9.3,7.7.HRMS calcd for C24H29O8[M+H]+:445.18569；found:445.18552.
9 1- of embodiment (3- (3- bytyry -2,6- dihydroxy -4- methoxyl group -5- methylbenzyl) -2,4,6- trihydroxy - 5- aminomethyl phenyl) hept- 1- ketone
2,4,6- trihydroxy -3- methylbenzene heptanone (13)
Yellow solid 13 is obtained referring to the synthetic method of intermediate 3, white solid, yield: 58%,1H-NMR(400MHz, Acetone-d6) δ 13.89 (s, 1H), 9.51 (s, 1H), 8.95 (s, 1H), 6.06 (s, 1H), 3.07 (t, J=7.4Hz, 2H), 1.96 (s, 3H), 1.63-1.70 (m, 2H), 1.29-1.40 (m, 6H), 0.88 (t, J=7.4Hz, 3H).
Referring to the synthetic method of embodiment 1, title compound is obtained by intermediate 13 and intermediate 6, faint yellow solid, is received Rate: 94-96 DEG C of 33%, mp,1H-NMR(400MHz,CDCl3)δ15.51(s,1H),9.53(s,1H),9.32(s,1H),3.83 (s,2H),3.70(s,3H),3.05-3.11(m,4H),2.10(s,3H),2.07(s,3H),1.63-1.78(m,4H),1.22- 1.43 (m, 8H), 0.98 (t, J=7.4Hz, 3H), 0.89 (t, J=6.7Hz, 3H)13C-NMR(100MHz,CDCl3)δ 207.0,206.9,161.7,160.1,159.8,159.5,112.1,109.5,107.8,105.7,103.9,101.8,61.5, 44.3,43.9,31.7,29.2,24.8,22.6,18.2,16.1,14.0,13.9,9.1,7.5.HRMS calcd for C24H29O8[M+H]+:489.24829；found:489.24826.
10 1- of embodiment (3- ((6,8- dihydroxy -9- methyl -5- propyl -2,3- dihydrobenzo [f] [1,4] oxygen nitrogen Zhuo - 7- yl) methyl) -2,4- dihydroxy -6- methoxyl group -5- aminomethyl phenyl) butane -1- ketone
2- (2-Boc amido) ethyoxyl -4,6- dimethoxy methoxyl group -3- methyl phenyl propyl ketone (14)
Intermediate 4 (0.5mmol), triphenylphosphine (1.25mmol) are dissolved in 2mL THF, and lower addition N-Boc is stirred at room temperature and protects The ethanol amine (1.25mmol) of shield, then DEAD (1.25mmol) slowly is added dropwise, 15min is reacted, is concentrated under reduced pressure, silica gel column chromatography (petrol ether/ethyl acetate=20:1) obtains colorless oil 14, yield: 79%,1H-NMR(300MHz,CDCl3)δ6.68(s, 1H), 5.16 (s, 2H), 5.10 (s, 2H), 3.87 (t, J=4.8Hz, 2H), 3.46 (s, 3H), 3.44 (s, 3H), 3.37-3.43 (m, 2H), 2.73 (t, J=7.2Hz, 2H), 2.06 (s, 3H), 1.65-1.72 (m, 2H), 1.43 (s, 9H), 0.95 (t, J= 7.2Hz,3H)。
9- methyl -5- propyl -2,3- dihydrobenzo [f] [Isosorbide-5-Nitrae] oxaza heptane -6,8- glycol (15)
Faint yellow solid 15 is obtained referring to the synthetic method of intermediate 6, yield: 67%,1H-NMR(300MHz,DMSO-d6) δ 13.51 (s, 1H), 11.13 (s, 1H), 11.01 (s, 1H), 6.61 (s, 1H), 4.55 (t, J=6.0Hz, 2H), 3.69 (t, J =6.0Hz, 2H), 3.16 (t, J=7.5Hz, 2H), 1.91 (s, 3H), 1.54-1.61 (m, 2H), 0.85 (t, J=6.9Hz, 3H)。
Referring to the synthetic method of embodiment 1, title compound is obtained by intermediate 15 and intermediate 6, yellow solid, is received Rate: 111-113 DEG C of 27%, mp,1H-NMR(400MHz,DMSO-d6)δ16.56(s,1H),15.75(s,1H),11.93(s, 1H),8.89(s,1H),4.41(brs,2H),3.61(s,3H),3.59(s,2H),3.58-3.61(m,2H),3.15(br, 2H), 2.96 (t, J=6.8Hz, 2H), 1.91 (s, 3H), 1.87 (s, 3H), 1.51-1.64 (m, 4H), 0.89 (t, J= 7.2Hz, 3H), 0.83 (t, J=7.2Hz, 3H)13C-NMR(150MHz,DMSO-d6):δ203.6,159.4,153.1, 112.9,112.0,110.4,77.0,61.0,44.5,42.7,38.0,21.1,21.0,18.3,18.1,13.8,13.4,9.3, 8.3.HRMS calcd for C26H34O7N[M+H]+:472.23298；found:472.23325.
11 3- of embodiment (2,6- dihydroxy -4- methoxyl group -3- methyl -5- (2- methylbutyryl) benzyl) -2,4,6- three Hydroxy-5-methyl benzaldehyde
2- hydroxy-3-methyl -4,6- dimethoxy methoxybenzene (2- methyl) butanone (16)
White solid 16 is obtained referring to the synthetic method of intermediate 4, yield: 85%,1H-NMR(300MHz,DMSO-d6)δ 13.38(s,1H),6.41(s,1H),5.31(s,2H),5.29(s,2H),3.60-3.66(m,1H),3.44(s,3H),3.40 (s, 3H), 1.96 (s, 3H), 1.68-1.80 (m, 1H), 1.27-1.42 (m, 1H), 1.10 (d, J=6.9Hz, 3H), 0.86 (t, J=7.2Hz, 3H).
3- methyl -2- methoxyl group -4,6- dimethoxy methoxybenzene (2- methyl) butanone (17)
Colorless oil 17 is obtained referring to the synthetic method of intermediate 5, yield: 87%,1H-NMR(300MHz,DMSO-d6) δ6.67(s,1H),5.21(s,2H),5.13(s,2H),3.60(s,3H),3.39(s,3H),3.34(s,3H),2.78-2.85 (m, 1H), 2.02 (s, 3H), 1.63-1.72 (m, 1H), 1.23-1.35 (m, 1H), 1.02 (d, J=6.9Hz, 3H), 0.86 (t, J=7.2Hz, 3H).
3- methyl -2- methoxyl group -4,6- dihydroxy benzenes (2- methyl) butanone (18)
Faint yellow solid 18 is obtained referring to the synthetic method of intermediate 6, yield 91%,1H-NMR(300MHz,DMSO-d6)δ 11.29(s,1H),10.14(s,1H),6.19(s,1H),3.63(s,3H),3.21-3.30(m,1H),1.94(s,3H), 1.62-1.71 (m, 1H), 1.26-1.36 (m, 1H), 1.04 (d, J=6.9Hz, 3H), 0.83 (t, J=7.2Hz, 3H).
Referring to the synthetic method of embodiment 1, title compound is obtained by intermediate 18 and intermediate 8, brown solid, is received Rate: 121-123 DEG C of 50%, mp,1H-NMR(400MHz,DMSO-d6)δ13.60(br,1H),11.41(br,1H),10.04 (br,1H),3.76(s,2H),3.65(s,3H),3.50-3.55(m,1H),2.04(s,3H),1.93(s,3H),1.64-1.73 (m, 1H), 1.29-1.38 (m, 1H), 1.09 (d, J=6.8Hz, 3H), 0.83 (d, J=7.4Hz, 3H)13C-NMR(101MHz, DMSO-d6)δ210.3,192.7,162.9,160.2,159.9,158.8,158.5,158.4,111.1,110.8,109.4, 105.9,105.9,103.4,62.5,45.5,267.0,17.1,16.8,12.2,9.8,8.4.HRMS calcd for C22H27O8[M+H]+:419.17004；found:419.16965.
12 1- of embodiment (three hydroxyl of 3- (3- bytyry -2,6- dihydroxy -4- isopropoxy -5- methylbenzyl) -2,4,6- Base -5- aminomethyl phenyl) -2- methybutane -1- ketone
3- methyl -2- isopropoxy -4,6- dimethoxy methoxybenzene (2- methyl) butanone (19)
Colorless oil 19 is obtained referring to the synthetic method of intermediate 14, yield: 81%,1H-NMR(400MHz, Acetone-d6)δ6.74(s,1H),5.23(s,2H),5.12(s,2H),4.13-4.21(m,1H),3.45(s,3H),3.41 (s, 3H), 2.71 (t, J=7.3Hz, 2H), 2.07 (s, 3H), 1.60-1.69 (m, 2H), 1.18 (d, J=6.1Hz, 6H), 0.95 (t, J=7.3Hz, 3H).
3- methyl -2- isopropoxy -4,6- dihydroxy benzenes (2- methyl) butanone (20)
White solid 20 is obtained referring to the synthetic method of intermediate 6, yield: 92%,1H-NMR(400MHz,CDCl3)δ 12.62 (d, J=4.3Hz, 1H), 6.49 (d, J=7.4Hz, 1H), 4.01-4.16 (m, 1H), 3.07 (t, J=7.4Hz, 2H), 2.07 (s, 3H), 1.63-1.72 (m, 2H), 1.25 (d, J=6.2Hz, 6H), 0.93 (t, J=7.3Hz, 3H).
Referring to the synthetic method of embodiment 1, title compound is obtained by intermediate 20 and intermediate 7, yellow solid, is received Rate: 65-66 DEG C of 44%, mp,1H-NMR(400MHz,CDCl3)δ15.63(s,1H),14.90(s,1H),9.50(s,1H), 9.34 (s, 1H), 4.09-4.14 (m, 1H), 3.82 (s, 2H), 3.76-3.82 (m, 1H), 3.11 (t, J=7.4Hz, 2H), 2.09(s,3H),2.07(s,3H),1.79-1.90(m,1H),1.64-1.73(m,2H),1.36-1.47(m,1H),1.24(d, J=6.1Hz, 3H), 1.17 (d, J=6.7Hz, 3H), 0.94 (t, J=7.6Hz, 3H), 0.92 (t, J=7.6Hz, 3H)13C- NMR(101MHz,DMSO-d6)δ211.0,207.2,160.1,159.9,159.5,158.1,156.8,156.3,112.0, 111.9,109.9,105.7,105.4,103.9,77.5,45.5,44.8,29.5,26.9,22.1,18.4,17.1,14.1, 12.3,10.7,9.1.HRMS calcd for C27H37O8[M+H]+:489.24829；found:489.24832.
13 1- of embodiment (3- (3- bytyry -4- (chloropropanol oxygen radical) -2,6- dihydroxy -5- methylbenzyl) -2,4,6- three Hydroxy-5-methyl base phenyl) -2- methybutane -1- ketone
2- (3- chlorine) propoxyl group -3- methyl -4,6- dimethoxy methoxybenzene (2- methyl) butanone (21)
Colorless oil 21 is obtained referring to the synthetic method of intermediate 14, yield: 78%,1H-NMR(300MHz,DMSO- d6) δ 6.68 (s, 1H), 5.21 (s, 2H), 5.14 (s, 2H), 3.83 (t, J=5.6Hz, 2H), 3.73 (t, J=6.3Hz, 2H), 3.39 (s, 3H), 3.34 (s, 3H), 2.68 (t, J=7.0Hz, 2H), 1.94-2.14 (m, 2H), 2.02 (s, 3H), 1.46- 1.66 (m, 2H), 0.90 (t, J=7.4Hz, 3H).
2- (3- chlorine) propoxyl group -3- methyl -4,6- dihydroxy benzenes (2- methyl) butanone (22)
Yellow solid 22 is obtained referring to the synthetic method of intermediate 6, yield: 89%,1H-NMR(300MHz,DMSO-d6)δ 11.88 (s, 1H), 10.30 (s, 1H), 6.17 (s, 1H), 3.78-3.85 (m, 4H), 2.89 (t, J=7.2Hz, 2H), 2.10- 2.18 (m, 2H), 1.93 (s, 3H), 1.47-1.66 (m, 2H), 0.88 (t, J=7.4Hz, 3H).
Referring to the synthetic method of embodiment 1, title compound is obtained by intermediate 22 and intermediate 7, yellow oil, is received Rate: 37%,1H-NMR(300MHz,CDCl3)δ15.71(s,1H),15.40(s,1H),9.60(s,1H),9.33(s,1H), 3.87 (t, J=6.0Hz, 2H), 3.76-3.87 (m, 1H), 3.83 (s, 2H), 3.78 (t, J=6.3Hz, 2H), 3.08 (t, J= 7.2Hz,2H),2.22-2.30(m,2H),2.09(s,3H),2.08(s,3H),1.80-1.89(m,1H),1.67-1.77(m, 2H), 1.34-1.48 (m, 1H), 1.17 (d, J=6.9Hz, 3H), 0.98 (t, J=7.5Hz, 3H), 0.89 (t, J=7.8Hz, 3H).13C-NMR(150MHz,CDCl3)δ211.0,206.7,161.7,160.3,159.4,158.6,112.3,109.7, 108.2,105.9,103.6,101.9,71.1,45.8,44.2,41.1,33.0,29.7,26.9,18.2,16.7,16.3, 13.9,12.0,9.2,7.5.HRMS calcd for C27H36ClO8[M+H]+:523.20932；found:523.21021.
14 N- of embodiment (3- (2- bytyry -3,5- dihydroxy -6- methyl -4- (2,4,6- trihydroxy -3- methyl -5- (2- methylbutyryl) benzyl) phenoxy group) propyl) acetamide
2- (3- amido) propoxyl group -3- methyl -4,6- dimethoxy methoxybenzene (2- methyl) butanone (23)
Colorless oil 23 is obtained referring to the synthetic method of intermediate 14, yield: 67%,1H-NMR(300MHz, Acetone-d6) δ 5.97 (s, 1H), 5.14 (br, 1H), 4.44 (s, 2H), 4.37 (s, 2H), 3.06 (t, J=6.0Hz, 2H), 2.66 (s, 3H), 2.63 (s, 3H), 2.40-2.46 (m, 2H), 1.95 (t, J=6.9Hz, 2H), 1.29 (s, 3H), 1.03- 1.12 (m, 2H), 0.81-0.93m, 2H), 0.17 (t, J=7.5Hz, 3H).
2- (3- amido) propoxyl group -3- methyl -4,6- dihydroxy benzenes (2- methyl) butanone (24)
Faint yellow solid 24 is obtained referring to the synthetic method of intermediate 6, yield: 81%,1H-NMR(300MHz,DMSO-d6) δ 11.72 (s, 1H), 10.41 (s, 1H), 8.07 (s, 3H), 6.26 (s, 1H), 3.80 (t, J=6.3Hz, 2H), 2.86-2.96 (m, 4H), 2.00-2.04 (m, 2H), 1.93 (s, 3H), 1.52-1.65 (m, 2H), 0.90 (t, J=7.2Hz, 3H).
2- (3- acetamido) propoxyl group -3- methyl -4,6- dihydroxy benzenes (2- methyl) butanone (25)
Intermediate 24 is reacted with acetic anhydride (1:1.2), obtains the product 25 of acetylation, faint yellow solid, yield: 95%,1H- NMR(300MHz,DMSO-d6) δ 12.03 (s, 1H), 10.34 (s, 1H), 7.86 (s, 1H), 6.17 (s, 1H), 3.73 (t, J= 6.0Hz, 2H), 3.16-3.22 (m, 2H), 2.90 (t, J=6.6Hz, 2H), 1.93 (s, 3H), 1.79-1.86 (m, 2H), 1.80 (s, 3H), 1.55-1.62 (m, 2H), 0.89 (t, J=7.2Hz, 3H).
Referring to the synthetic method of embodiment 1, title compound is obtained by intermediate 25 and intermediate 7, yellow solid, is received Rate: 67-69 DEG C of 33%, mp,1H-NMR(400MHz,DMSO-d6)δ14.16(br,2H),11.75(br,2H),7.87(s, 1H), 3.86 (dd, J=13.2Hz, 6.7Hz, 2H), 3.65-3.75 (m, 5H), 3.16-3.22 (m, 2H), 3.02 (t, J= 7.2Hz,2H),2.02(s,3H),1.95(s,3H),1.85-1.91(m,2H),1.79(s,3H),1.59-1.64(m,2H), 1.31-1.36 (m, 2H), 1.09 (d, J=6.7Hz, 3H), 0.92-0.84 (m, 6H)13C-NMR(101MHz,DMSO-d6)δ 210.9,206.7,169.6,160.2,160.1,159.8,158.3,158.2,158.1,111.5,110.5,109.9, 105.7,105.4,103.9,73.0,45.6,44.4,36.0,30.2,26.9,23.0,18.0,17.2,17.0,14.1, 12.2,9.8,8.9.HRMS calcd for C29H40O9N[M+H]+:546.26976；found:546.27026.
15 1- of embodiment (3- (3- bytyry -2,6- dihydroxy -5- methyl -4- (2- propine -1- oxygroup) benzyl) -2,4, 6- trihydroxy -5- aminomethyl phenyl) -2- methybutane -1- ketone
2- propargyl alcoholate -3- methyl -4,6- dimethoxy methoxybenzene (2- methyl) butanone (26)
Colorless oil 26 is obtained referring to the synthetic method of intermediate 14, yield: 66%,1H-NMR(300MHz, Acetone-d6) δ 6.80 (s, 1H), 5.24 (s, 2H), 5.17 (s, 2H), 4.52 (d, J=2.4Hz, 2H), 3.45 (s, 3H), 3.422 (s, 3H), 2.75 (t, J=7.2Hz, 2H), 2.13 (s, 3H), 1.59-1.72 (m, 2H), 0.95 (t, J=7.5Hz, 3H)。
2- propargyl alcoholate -3- methyl -4,6- dihydroxy benzenes (2- methyl) butanone (27)
White solid 27 is obtained referring to the synthetic method of intermediate 6, yield: 83%,1H-NMR(300MHz,Acetone- d6) δ 13.10 (s, 1H), 9.46 (s, 1H), 6.24 (s, 1H), 4.65 (d, J=2.4Hz, 2H), 3.12-3.17 (m, 3H), 2.10 (s, 3H), 1.65-1.72 (m, 2H), 0.95 (t, J=7.5Hz, 3H).
Referring to the synthetic method of embodiment 1, title compound is obtained by intermediate 27 and intermediate 7, faint yellow solid, is received Rate: 93-95 DEG C of 58%, mp,1H-NMR(400MHz,DMSO-d6)δ14.26(s,1H),11.76(s,1H),4.59(s,2H), 4.04-4.25 (m, 2H), 3.87 (dd, J=13.3Hz, 6.7Hz, 1H), 3.77 (s, 2H), 3.64 (t, J=2.4Hz, 1H), 3.09 (t, J=7.3Hz, 2H), 2.05 (s, 3H), 1.96 (s, 3H), 1.70-1.79 (m, 1H), 1.62 (dd, J=14.6Hz, 7.3Hz, 2H), 1.35 (dd, J=13.8Hz, 6.8Hz, 1H), 1.16 (d, J=7.0Hz, 1H), 1.09 (d, J=6.7Hz, 3H), 0.92 (t, J=7.4Hz, 3H), 0.85 (t, J=7.4Hz, 3H)13C-NMR(101MHz,DMSO-d6)δ210.9, 206.9,160.4,160.1,159.8,158.5,158.2,156.8,111.7,110.9,109.9,105.6,105.3, 103.9,79.8,79.2,61.9,45.6,44.9,27.0,18.1,17.2,14.7,14.1,12.3,10.1,9.0.HRMS calcd for C27H33O8[M+H]+:485.21699；found:485.21707.
Embodiment 16 1,1 '-(di-2-ethylhexylphosphine oxide (2,4,6- trihydroxy -3- methyl -5,1- phenylene)) bis- (butane -1- ketone)
Referring to the synthetic method of embodiment 1, title compound is obtained by intermediate 3, faint yellow solid, yield: 89%, mp 152-154 DEG C,1H-NMR(400MHz,CDCl3) δ 15.50 (s, 2H), 9.31 (s, 2H), 3.79 (s, 2H), 3.07 (t, J= 7.3Hz, 4H), 2.07 (s, 6H), 1.68-1.75 (m, J=14.5Hz, 7.3Hz, 5H), 0.99 (t, J=7.3Hz, 7H)13C- NMR(100MHz,CDCl3)δ206.9,160.5,159.9,156.4,106.3,103.9,101.9,46.0,18.3,16.1, 14.2,7.6.HRMS calcd for C23H29O8[M+H]+:433.18624；found:433.18607.
17 1- of embodiment (3- (3- bytyry -2,6- dihydroxy -4- methoxyl group -5- methylbenzyl) -2,4- dihydroxy -6- Methoxyl group -5- aminomethyl phenyl) -2- methybutane -1- ketone
Referring to the synthetic method of embodiment 1, title compound is obtained by intermediate 6 and intermediate 18, yellow solid, is received Rate: 97-99 DEG C of 44%, mp,1H-NMR(400MHz,DMSO-d6)δ14.19(br,1H),13.31(br,1H),9.78(br, 2H), 3.81 (s, 2H), 3.66 (s, 3H), 3.64 (s, 3H), 3.47-3.53 (m, 1H), 3.02 (t, J=7.0Hz, 2H), 2.03 (s, 3H), 2.02 (s, 3H), 1.58-1.73 (m, 3H), 1.37 (d, J=7.2Hz, 1H), 1.08 (d, J=6.8Hz, 3H), 0.91 (t, J=7.4Hz, 3H), 0.84 (t, J=7.4Hz, 3H)13C-NMR(101MHz,DMSO-d6)δ210.3,206.6, 160.7,159.9,159.5,158.6,158.3,158.2,110.9,110.8,110.2,109.9,109.8,108.9,62.5, 61.9,45.7,44.4,26.9,18.0,17.1,16.9,14.2,12.2,9.7,9.7.HRMS calcd for C26H35O8[M+ H]+:475.23264；found:475.23254.
18 1- of embodiment (3- (3- bytyry -2,4,6- trihydroxy -5- methylbenzyl) -2,4- dihydroxy -6- methoxyl group - 5- aminomethyl phenyl) -2- methybutane -1- ketone
Referring to the synthetic method of embodiment 1, title compound is obtained by intermediate 3 and intermediate 18, yellow solid, is received Rate: 81-83 DEG C of 44%, mp,1H-NMR(400MHz,DMSO-d6)δ13.56(s,1H),11.87(s,1H),9.95(br,3H), 3.76 (s, 2H), 3.65 (s, 3H), 3.49 (dd, J=13.3Hz, 6.7Hz, 1H), 3.07 (t, J=7.3Hz, 2H), 2.04 (s, 3H), 1.96 (s, 3H), 1.58-1.74 (m, 3H), 1.31-1.40 (m, 1H), 1.08 (d, J=6.8Hz, 3H), 0.92 (t, J= 7.4Hz, 3H), 0.84 (t, J=7.4Hz, 3H)13C-NMR(101MHz,DMSO-d6)δ210.4,206.9,160.1,156.0, 159.7,158.7,158.2,157.7,111.3,110.8,109.9,105.6,105.5,103.8,62.5,45.9,45.7, 40.6,40.4,40.2,39.9,39.7,39.5,39.3,26.9,18.2,17.1,14.3,12.2,9.8,9.0.HRMS calcd for C25H32O8[M+H]+:461.21699；found:461.21677.
Embodiment 19 1,1 '-(di-2-ethylhexylphosphine oxide (4,6- dihydroxy -2- methoxyl group -3- methyl -5,1- phenylene)) bis- (2- Methybutane -1- ketone)
Referring to the synthetic method of embodiment 1, title compound is obtained by intermediate 18, yellow solid, yield: 21%, mp 115-117 DEG C,1H-NMR(400MHz,DMSO-d6)δ13.27(br,2H),9.86(br,2H),3.81(s,2H),3.64(s, 6H), 3.47-3.53 (m, 2H), 1.66-1.73 (m, 2H), 1.29-1.39 (m, 2H), 1.08 (d, J=6.8Hz, 6H), 0.84 (t, J=7.4Hz, 6H)13C-NMR(101MHz,DMSO-d6)δ210.3,159.8,158.6,158.1,110.9,110.3, 109.9,62.5,45.7,26.9,26.9,17.2,17.1,12.2,9.8.HRMS calcd for C27H37O8[M+H]+: 489.24811；found:489.24829.
Embodiment 20 1,1 '-(di-2-ethylhexylphosphine oxide (4,6- dihydroxy -2- methoxyl group -3- methyl -5,1- phenylene)) bis- (fourths Alkane -1- ketone)
Referring to the synthetic method of embodiment 1, title compound is obtained by intermediate 6, yellow solid, yield: 89%, mp 137-139 DEG C,1H-NMR(400MHz,DMSO-d6)δ14.01(br,2H),9.57(br,2H),3.82(s,2H),3.66(s, 6H), 3.02 (t, J=7.2Hz, 4H), 2.02 (s, 6H), 1.56-1.65 (m, 4H), 0.91 (t, J=7.4Hz, 6H)13C-NMR (101MHz,DMSO-d6)δ206.5,160.7,159.5,159.4,110.8,109.9,108.9,62.0,44.4,18.0, 16.8,14.2,9.7.HRMS calcd for C25H33O8[M+H]+:461.21699；found:461.21698.
21 1- of embodiment (3- (3- bytyry -2,4,6- trimethoxy -5- methylbenzyl) -2,4,6- trimethoxy -5- Aminomethyl phenyl) -2- methyl butyl- 1- ketone
The compound (0.5mmol) of embodiment 1 is dissolved in 5mL acetone, and lower addition potassium carbonate (3.0mmol) is stirred at room temperature, Dimethyl suflfate (3.0mmol) is added in 2min, and flow back 3h after 5min, cooling, crosses and filters out, filtrate decompression concentration, silica gel column chromatography (petrol ether/ethyl acetate=30:1) title compound, light yellow oil, yield: 85%,1H-NMR(400MHz, CDCl3)δ3.98(s,2H),3.68(s,5H),3.55(s,3H),3.53(s,3H),3.50(s,3H),3.47(s,3H), 2.86-2.91 (m, 1H), 2.74 (t, J=7.1Hz, 2H), 2.14 (s, 6H), 1.74-1.83 (m, 1H), 1.31-1.44 (m, 2H), 1.63-1.73 (m, 1H), 1.11 (d, J=6.9Hz, 3H), 0.95 (t, J=7.3Hz, 3H), 0.91 (t, J=7.3Hz, 3H).13C-NMR(100MHz,CDCl3)δ209.2,205.7,159.2,159.2,154.5,154.2,154.1,153.9, 127.3,127.0,124.7,121.0,120.9,63.1,63.0,62.6,62.5,60.4,60.3,49.2,47.1,25.2, 19.5,17.2,15.1,13.8,11.7,9.7,9.6.HRMS calcd for C30H43O8[M+H]+:531.29524；found: 531.29596。
22 2- of embodiment (2,6- diacetoxy -3- bytyry -4- methoxyl group -5- methylbenzyl) -4- methyl -6- (2- Methylbutyryl) benzene -1,3,5- triacetate
The compound (0.5mmol) of embodiment 1 is dissolved in 5mL DCM, and lower addition TEA (3.0mmol), acetic anhydride is stirred at room temperature (3.0mmol) after stirring 2h, is concentrated under reduced pressure, and silica gel column chromatography (petrol ether/ethyl acetate=50:1) obtains title compound, light Yellow solid, yield: 163-165 DEG C of 79%, mp,1H-NMR(400MHz,CDCl3)δ3.67(s,3H),3.46(s,2H), 2.78 (t, J=7.2Hz, 2H), 2.68-2.74 (m, 1H), 2.24 (s, 3H), 2.23 (s, 3H), 2.19 (s, 3H), 2.14 (s, 3H),2.13(s,3H),2.00(s,3H),1.86(s,3H),1.58-1.79(m,3H),1.29-1.39(m,1H),1.07(d,J =6.9Hz, 3H), 0.95 (t, J=7.4Hz, 3H), 0.89 (t, J=7.4Hz, 3H)13C-NMR(100MHz,CDCl3)δ 204.5,203.4,168.7,168.1,167.9,167.8,167.8,154.9,149.8,149.5,145.3,144.5, 143.7,127.5,126.7,124.3,123.6,123.4,121.5,62.7,48.4,45.9,25.2,21.8,20.6,20.5, 20.4,17.1,15.1,13.8,11.6,10.8,9.9.HRMS calcd for C35H43O13[M+H]+:671.26982； found:671.26986。
23 1- of embodiment (3- (3- bytyry -6- hydroxyl -2,4- dimethoxy -5- methylbenzyl) -2,4,6- trihydroxy - 5- aminomethyl phenyl) -2- methybutane -1- ketone
2- methoxyl group -3- methyl -4- methoxymethoxy -6- hydroxyl-phenyl propyl ketone (28)
Intermediate 28 is obtained referring to the synthetic method of intermediate 4, colorless oil, yield: 83%,1H-NMR(500MHz, Acetone-d6)δ13.14(s,1H),6.41(s,1H),5.30(s,2H),3.78(s,3H),3.46(s,3H),3.09(t,J =7.2Hz, 2H), 2.08 (s, 3H), 1.63-1.74 (m, 2H), 0.96 (t, J=7.4Hz, 3H).
2,6- dimethoxy -3- methyl -4- methoxymethoxies-phenyl propyl ketone (29)
Intermediate 29 is obtained referring to the synthetic method of intermediate 5, colorless oil, yield: 88%,1H-NMR(500MHz, Acetone-d6) δ 6.64 (s, 1H), 5.27 (s, 2H), 3.78 (s, 3H), 3.67 (s, 3H), 3.46 (s, 3H), 2.67 (t, J= 7.2Hz, 2H), 2.06 (s, 3H), 1.55-1.69 (m, 2H), 0.94 (t, J=7.4Hz, 4H).
2,6- dimethoxy -3- methyl -4- hydroxyls-phenyl propyl ketone (30)
Intermediate 30 is obtained referring to the synthetic method of intermediate 6, white solid, yield: 91%,1H-NMR(300MHz, Acetone-d6) δ 8.57 (s, 1H), 6.37 (s, 1H), 3.72 (s, 3H), 3.67 (s, 3H), 2.67 (t, J=7.2Hz, 2H), 2.05 (s, 3H), 1.60-1.66 (m, 2H), 0.93 (t, J=7.2Hz, 3H).
Referring to the synthetic method of embodiment 1, title compound is obtained by intermediate 30 and intermediate 7, dark green solid, is received Rate: 67-69 DEG C of 42%, mp,1H-NMR(400MHz,DMSO-d6)δ11.97(br,1H),11.58(s,1H),9.39(br, 1H), 3.79 (s, 2H), 3.65 (s, 3H), 3.58 (s, 3H), 2.70 (t, J=7.1Hz, 2H), 2.03 (s, 3H), 1.96 (s, 3H), 1.69-1.77 (m, 1H), 1.54-1.59 (m, 2H), 1.31-1.38 (m, 1H), 1.09 (d, J=6.7Hz, 3H), 0.91 (t, J=7.4Hz, 3H), 0.84 (t, J=7.4Hz, 3H)13C-NMR(101MHz,DMSO-d6)δ210.9,204.3,160.3, 159.5,158.5,155.2,154.4,152.8,122.7,116.8,115.1,105.8,105.4,103.5,63.9,62.4, 46.7,45.6,27.1,17.7,17.3,17.2,13.9,12.3,9.8,9.1.HRMS calcd for C26H35O8[M+H]+: 475.23264；found:475.23239.
24 1- of embodiment (3- (3- bytyry -2,6- dihydroxy -4- methoxyl group -5- methylbenzyl) -4- hydroxyl -2,6- two Methoxyl group -5- aminomethyl phenyl) -2- methybutane -1- ketone
2- methoxyl group -3- methyl -4- methoxymethoxy -6- hydroxyl-benzene (2- methyl) butanone (31)
Intermediate 31 is obtained referring to the synthetic method of intermediate 4, colorless oil, yield: 77%,1H-NMR(300MHz, Acetone-d6)δ12.74(s,1H),6.43(s,1H),5.30(s,2H),3.77(s,3H),3.67-3.87(m,1H),3.47 (s, 3H), 2.09 (s, 3H), 1.71-1.82 (m, 1H), 1.36-1.45 (m, 1H), 1.14 (d, J=6.6Hz, 3H), 0.88 (t, J=7.2Hz, 3H).
2,6- dimethoxy -3- methyl -4- methoxymethoxies-benzene (2- methyl) butanone (32)
Intermediate 32 is obtained referring to the synthetic method of intermediate 5, colorless oil, yield: 84%,1H-NMR(300MHz, Acetone-d6)δ6.62(s,1H),5.26(s,2H),3.76(s,3H),3.65(s,3H),3.45(s,3H),2.76-2.85 (m, 1H), 2.05 (s, 3H), 1.66-1.73 (m, 1H), 1.27-1.37 (m, 1H), 1.04 (d, J=6.6Hz, 3H), 0.88 (t, J=7.2Hz, 3H).
2,6- dimethoxy -3- methyl -4- hydroxyls-benzene (2- methyl) butanone (33)
Intermediate 33 is obtained referring to the synthetic method of intermediate 6, white solid, yield: 89%,1H-NMR(300MHz, Acetone-d6)δ8.26(s,1H),6.09(s,1H),3.42(s,3H),3.38(s,3H),2.53-2.59(m,1H),1.76 (s, 3H), 1.38-1.45 (m, 1H), 0.99-1.09 (m, 1H), 0.76 (d, J=6.6Hz, 3H), 0.60 (t, J=7.2Hz, 3H)。
3- ((dimethyl amido) methyl) -2,4- dihydroxy -6- methoxyl group -5- methyl phenyl propyl ketone (34)
At room temperature, N, N, N, N- tetramethyl methanediamine is added into DCM (3mL) solution of intermediate 6 (0.5mmol) (0.6mmol) stirs 2h, is concentrated under reduced pressure, and silica gel column chromatography (DCM/MeOH=100:1) obtains title compound, and white solid is received Rate: 98%,1H-NMR(400MHz,CDCl3) δ 3.77 (s, 2H), 3.72 (s, 3H), 3.04 (t, J=7.3Hz, 2H), 2.37 (s, 6H), 2.07 (s, 3H), 1.62-1.79 (m, 2H), 0.97 (t, J=7.4Hz, 3H).
At room temperature, to intermediate 33 (0.1mmol), Isosorbide-5-Nitrae-dioxane (2mL) solution of intermediate 34 (0.12mmol) Middle addition anhydrous zinc chloride (0.5mmol), flow back 8h, is concentrated under reduced pressure, after silica gel column chromatography (petrol ether/ethyl acetate=40:1) Title compound, faint yellow solid, yield: 69-71 DEG C of 36%, mp,1H-NMR(400MHz,DMSO-d6)δ13.80(br, 1H), 9.22 (br, 2H), 3.84 (s, 2H), 3.66 (s, 3H), 3.57 (d, J=2.9Hz, 6H), 3.02 (t, J=7.2Hz, 2H), 2.75-2.85 (m, 1H), 2.02 (d, J=1.5Hz, 6H), 1.61-1.64 (m, 2H), 1.23-1.41 (m, 2H), 1.01 (d, J=7.0Hz, 3H), 0.91 (t, J=3.7Hz, 3H), 0.85 (t, J=7.4Hz, 3H)13C-NMR(101MHz,DMSO- d6)δ207.8,206.4,160.9,160.1,159.4,155.6,154.4,153.5,122.3,116.8,114.7,110.3, 110.1,108.7,63.8,62.6,62.0,48.6,44.4,25.2,18.1,17.7,15.6,14.2,11.9,9.8,9.7。
25 1- of embodiment (3- (5- bytyry -2- hydroxyl -4- methoxyl group -3- methylbenzyl) -2,4,6- trihydroxy -5- first Base phenyl) -2- methybutane -1- ketone
2,4- dihydroxy -3- methyl phenyl propyl ketones (35)
Referring to the synthetic method of intermediate 3, with 2- methyl-1,3- benzenediol is that raw material obtains intermediate 35, white solid, Yield: 75%,1H-NMR(400MHz,Acetone-d6) δ 13.21 (s, 1H), 9.18 (s, 1H), 7.67 (d, J=8.8Hz, 1H), 6.49 (d, J=8.8Hz, 1H), 2.93 (t, J=7.3Hz, 2H), 2.06 (s, 3H), 1.62-1.79 (m, 2H), 0.98 (t, J=7.4Hz, 3H).
4- methoxymethoxy -2- hydroxy-3-methyl phenyl propyl ketone (36)
Intermediate 36 is obtained referring to the synthetic method of intermediate 4, colorless oil, yield: 87%,1H-NMR(400MHz, CDCl3) δ 12.95 (s, 1H), 7.60 (d, J=9.0Hz, 1H), 6.64 (d, J=9.0Hz, 1H), 3.49 (s, 3H), 2.89 (t, J=7.4Hz, 2H), 2.13 (s, 3H), 1.69-1.85 (m, 2H), 1.01 (t, J=7.4Hz, 3H).
4- methoxymethoxy -2- methoxyl group -3- methyl phenyl propyl ketone (37)
Intermediate 37 is obtained referring to the synthetic method of intermediate 5, white solid, yield: 90%,1H-NMR(400MHz, CDCl3) δ 7.45 (d, J=8.7Hz, 1H), 6.88 (d, J=8.7Hz, 1H), 5.23 (s, 2H), 3.74 (s, 3H), 3.48 (s, 3H), 2.93 (t, J=7.3Hz, 2H), 2.19 (s, 3H), 1.64-1.78 (m, 2H), 0.96 (t, J=7.4Hz, 3H).
2- methoxyl group -4- hydroxy-3-methyl phenyl propyl ketone (38)
Intermediate 38 is obtained referring to the synthetic method of intermediate 6, white solid, yield: 92%,1H-NMR(400MHz, Acetone-d6) δ 8.92 (s, 1H), 7.38 (d, J=8.5Hz, 1H), 6.70 (d, J=8.5Hz, 1H), 2.91 (t, J= 7.2Hz, 2H), 2.15 (s, 3H), 1.59-1.71 (m, 2H), 0.93 (t, J=7.4Hz, 3H).
Referring to the synthetic method of embodiment 1, title compound is obtained by intermediate 38 and intermediate 7, faint yellow solid, is received Rate: 32%, mp109-111 DEG C,1H-NMR(400MHz,Acetone-d6)δ13.06(s,1H),10.08(s,1H),8.73(s, 2H), 7.55 (s, 1H), 3.85-3.98 (m, 1H), 3.90 (s, 2H), 3.69 (s, 3H), 2.87 (t, J=7.2Hz, 2H), 2.18 (s, 3H), 2.14 (s, 3H), 1.76-1.91 (m, 1H), 1.57-1.69 (m, 2H), 1.32-1.45 (m, 1H), 1.13 (d, J= 6.7Hz, 3H), 0.91 (t, J=6.6Hz, 3H), 0.87 (t, J=6.6Hz, 3H)13C-NMR(100MHz,CDCl3)δ211.5, 203.7,159.9,158.9,157.9,157.7,156.9,130.6,124.5,122.3,119.2,106.7,105.0, 101.6,62.1,46.3,44.1,30.8,27.2,18.3,16.9,14.1,12.2,9.4,8.0.HRMS calcd for C25H33O7[M+H]+:445.22208；found:445.22211.
26 1- of embodiment (5- (3- bytyry -2,6- dihydroxy -4- methoxyl group -5- methylbenzyl) -2,4- dihydroxy -3- Aminomethyl phenyl) -2- methybutane -1- ketone
2,4- dihydroxy -3- methyl-benzene (2- methyl) butanone (39)
Referring to the synthetic method of intermediate 3, with 2- methyl-1,3- benzenediol is that raw material obtains intermediate 39, white solid, Yield: 78%,1H-NMR(400MHz,CDCl3) δ 13.42 (s, 1H), 7.58 (d, J=8.8Hz, 1H), 6.39 (d, J= 8.8Hz,1H),3.31-3.39(m,1H),2.14(s,3H),1.73-1.89(m,1H),1.42-1.60(m,1H),1.20(d,J =6.8Hz, 3H), 0.92 (t, J=7.4Hz, 3H).
Referring to the synthetic method of embodiment 1, title compound is obtained by intermediate 38 and intermediate 7, yellow solid, is received Rate: 105-107 DEG C of 34%, mp,1H-NMR(400MHz,CDCl3)δ14.47(s,1H),13.14(s,1H),7.88(s,1H), 7.82 (s, 1H), 6.24 (s, 1H), 3.32-3.46 (m, 1H), 3.06 (t, J=7.3Hz, 2H), 2.13 (s, 3H), 2.11 (s, 3H), 1.80-1.89 (m, 1H), 1.68-1.77 (m, 2H), 1.46-1.57 (m, 1H), 1.21 (d, J=6.8Hz, 3H), 0.97 (t, J=7.4Hz, 3H), 0.93 (t, J=7.4Hz, 3H)13C-NMR(100MHz,CDCl3)δ209.3,207.1,162.3, 160.2,160.1,159.1,158.9,130.8,116.9,112,6,112.1,110.6,109.4,109.3,62.1,44.7, 41.5,29.9,27.3,23.7,18.3,17.4,14.0,12.0,8.8,7.9.HRMS calcd for C25H33O7[M+H]+: 445.22208；found:445.22162.
27 1- of embodiment (3- (3- bytyry-2,6- dihydroxy-4- methoxyl group-5- methylbenzyl) dihydroxy-2-4,6-, 5- Dimethoxyphenyl) -2- methybutane -1- ketone
2,4- dihydroxy -3,6- dimethyl-benzene (2- methyl) butanone (40)
It is that raw material obtains intermediate 40, brown with 2,5- dimethyl-Resorcinol referring to the synthetic method of intermediate 3 Solid, yield: 84%,1H-NMR(400MHz,Acetone-d6)δ12.19(s,1H),8.85(s,1H),6.34(s,1H), 3.35-3.43(m,1H),2.47(s,3H),2.04(s,3H),1.69-1.84(m,1H),1.37-1.48(m,1H),1.14(d, J=6.7Hz, 3H), 0.86 (t, J=7.4Hz, 3H).
Referring to the synthetic method of embodiment 1, title compound is obtained by intermediate 38 and intermediate 7, red solid, is received Rate: 59-61 DEG C of 38%, mp,1H-NMR(400MHz,CDCl3)δ14.35(s,1H),10.29(s,1H),6.85(s,1H), 6.77 (s, 1H), 3.94 (s, 2H), 3.71 (s, 3H), 3.12-3.15 (m, 1H), 3.07 (t, J=7.2Hz, 2H), 2.54 (s, 3H),2.10(s,3H),2.09(s,3H),1.66-1.78(m,2H),1.41-1.50(m,1H),1.41-1.42(m,1H), 1.16 (d, J=6.5Hz, 3H), 0.98 (t, J=7.3Hz, 3H), 0.82 (t, J=7.2Hz, 3H)13C-NMR(101MHz, DMSO)δ211.7,206.5,161.2,160.6,159.5,153.7,151.2,132.5,125.2,118.6,110.7, 110.4,110.2,108.3,61.9,48.4,44.4,25.4,20.2,18.2,16.8,15.6,14.2,12.1,10.0, 9.7.HRMS calcd for C26H35O7[M+H]+:459.23773；found:459.23749.
28 1- of embodiment (3- (3- bytyry -2,6- dihydroxy -4- methoxyl group -5- methylbenzyl) -2- hydroxyl -4,6- two Methoxyl group -5- aminomethyl phenyl) butane -1- ketone
Referring to the synthetic method of embodiment 21, title compound is obtained by the title compound of embodiment 20, pale yellow colored solid Body, yield: 108-110 DEG C of 45%, mp,1H-NMR(400MHz,CDCl3)δ14.38(s,1H),12.38(s,1H),8.81(s, 1H), 3.91 (s, 2H), 3.83 (s, 3H), 3.72 (s, 3H), 3.69 (s, 3H), 3.05 (t, J=7.3Hz, 2H), 2.98 (t, J =7.3Hz, 2H), 2.16 (s, 3H), 2.07 (s, 3H), 1.65-1.81 (m, 4H), 0.98 (t, J=7.4Hz, 6H)13C-NMR (100MHz,CDCl3)δ207.1,206.6,161.6,161.3,160.9,160.0,158.8,156.6,116.7,116.6, 115.7,110.9,109.2,108.5,62.0,61.7,61.3,45.7,44.7,18.5,17.8,16.7,14.1,14.0, 9.7,9.2.HRMS calcd for C26H35O8[M+H]+:475.23264；found:475.23248.
29 1- of embodiment (3- (3- bytyry -2- hydroxyl -4,6- dimethoxy -5- methylbenzyl) -4- hydroxyl -2,6- two Methoxyl group -5- aminomethyl phenyl) butane -1- ketone
Referring to the synthetic method of embodiment 21, title compound is obtained by the title compound of embodiment 20, pale yellow colored solid Body, yield: 90-92 DEG C of 35%, mp,1H-NMR(400MHz,CDCl3)δ13.98(s,1H),8.45(s,1H),3.92(s, 2H), 3.81 (s, 3H), 3.74 (s, 3H), 3.69 (s, 3H), 3.68 (s, 3H), 3.05 (t, J=7.3Hz, 2H), 2.76 (t, J =7.2Hz, 2H), 2.18 (s, 3H), 2.05 (s, 3H), 1.62-1.79 (m, 4H), 0.97 (t, J=7.4Hz, 6H)13C-NMR (100MHz,CDCl3)δ206.5,205.3,161.6,161.1,160.0,158.2,155.0,153.1,128.1,122.6, 121.9,110.2,108.8,108.5,64.1,62.6,61.7,61.4,47.18,44.8,18.5,17.1,16.9,14.1, 13.8,9.6,9.1.HRMS calcd for C27H36O8[M+H]+:489.24829；found:489.24829.
30 1- of embodiment (3- (3- bytyry -2,4,6- trimethoxy -5- methylbenzyl) -2- hydroxyl -4,6- dimethoxy Base -5- aminomethyl phenyl) butane -1- ketone
Referring to the synthetic method of embodiment 21, title compound is obtained by the title compound of embodiment 20, pale yellow colored solid Body, yield: 75-77 DEG C of 41%, mp,1H-NMR(400MHz,CDCl3)δ13.07(s,1H),4.00(s,2H),3.71(s, 3H), 3.69 (s, 3H), 3.58 (s, 3H), 3.56 (s, 3H), 3.48 (s, 3H), 3.06 (t, J=7.3Hz, 2H), 2.76 (t, J =7.3Hz, 2H), 2.14 (s, 3H), 2.13 (s, 3H), 1.63-1.77 (m, 4H), 0.96 (t, J=7.4,6H)13C-NMR (100MHz,CDCl3)δ207.5,205.9,163.9,160.9,159.6,159.3,154.0,153.9,127.3,124.7, 120.9,119.1,115.3,111.8,63.1,62.6,61.8,60.6,60.3,47.1,45.2,18.8,18.3,17.2, 14.0,13.8,9.7,9.6.HRMS calcd for C28H39O8[M+H]+:503.26394；found:503.26379.
Embodiment 31 1,1 '-(di-2-ethylhexylphosphine oxide (2,4,6- trimethoxy -3- methyl -5,1- phenylene)) bis- (butane -1- Ketone)
Referring to the synthetic method of embodiment 21, title compound is obtained by the title compound of embodiment 20, faint yellow oil Shape object, yield: 88%,1H-NMR(400MHz,CDCl3)δ3.98(s,2H),3.69(s,6H),3.52(s,6H),3.50(s, 6H), 2.75 (t, J=7.3Hz, 4H), 2.15 (s, 6H), 1.62-1.76 (m, 4H), 0.96 (t, J=7.4Hz, 6H)13C-NMR (150MHz,CDCl3)δ205.5,159.0,154.0,153.7,127.1,124.5,120.7,62.8,62.4,60.2,46.9, 19.3,17.0,13.6,9.4.HRMS calcd for C29H40O8[M+H]+:517.27959；found:517.28040.
32 4- bytyry -2- of embodiment (3- bytyry -2,6- dihydroxy -4- methoxyl group -5- methylbenzyl) -3- hydroxyl - 5- methoxyl group -6- aminomethyl phenyl acetic acid esters
Referring to the synthetic method of embodiment 22, title compound is obtained by the title compound of embodiment 20, pale yellow colored solid Body, yield: 122-124 DEG C of 40%, mp,1H-NMR(400MHz,CDCl3)δ14.61(s,1H),14.16(s,1H),8.79(s, 1H), 3.91 (s, 2H), 3.74 (s, 3H), 3.68 (s, 3H), 3.12 (t, J=7.0Hz, 2H), 3.06 (t, J=7.3Hz, 2H), 2.38 (s, 3H), 2.05 (s, 3H), 1.99 (s, 3H), 1.65-1.81 (m, 4H), 0.99 (t, J=7.4Hz, 3H), 0.98 (t, J =7.4Hz, 3H)13C-NMR(100MHz,CDCl3)δ208.5,206.7,168.6,161.7,161.5,160.1,159.8, 158.5,155.5,117.9,117.5,113.0,110.6,108.5,108.2,62.1,61.7,45.3,44.7,21.2, 18.5,18.0,16.3,14.1,14.0,9.9,9.2.HRMS calcd for C27H34O9[M+H]+:503.22756；found: 503.22739。
33 2- of embodiment (2- acetoxyl group -5- bytyry -6- hydroxyl -4- methoxyl group -3- methylbenzyl) -4- bytyry - 5- methoxyl group -6- methyl-1,3- phenylenediacetic acid ester
Referring to the synthetic method of embodiment 22, title compound is obtained by the title compound of embodiment 20, pale yellow colored solid Body, yield: 46-48 DEG C of 43%, mp,1H-NMR(400MHz,CDCl3)δ13.07(s,1H),3.72(s,3H),3.68(s, 3H), 3.09 (t, J=7.3Hz, 2H), 2.80 (t, J=7.2Hz, 2H), 2.29 (s, 3H), 2.15 (s, 3H), 2.12 (s, 3H), 2.00 (s, 3H), 1.95 (s, 3H), 1.69-1.78 (m, 2H), 1.62-1.69 (m, 2H), 0.98 (t, J=7.3Hz, 3H), 0.94 (t, J=7.3Hz, 3H)13C-NMR(100MHz,CDCl3)δ207.7,203.7,168.7,168.4,167.9,160.0, 159.4,154.5,154.5,150.0,143.9,127.4,123.1,122.9,117.2,115.5,113.2,62.7,62.2, 45.9,45.3,20.8,20.6,20.5,19.6,18.1,17.1,14.0,13.8,9.9,9.6.HRMS calcd for C31H39O11[M+H]+:587.24869；found:587.24823.
34 2- of embodiment (2,6- diacetoxy -5- bytyry -6- hydroxyl -4- methoxyl group -3- methylbenzyl) -4- fourth Acyl group -5- methoxyl group -6- methyl-1,3- phenylenediacetic acid ester
Referring to the synthetic method of embodiment 22, title compound is obtained by the title compound of embodiment 20, pale yellow colored solid Body, yield: 105-107 DEG C of 79%, mp,1H-NMR(400MHz,CDCl3)δ3.67(s,6H),3.44(s,2H),2.78(t,J =7.2Hz, 4H), 2.24 (s, 6H), 2.16 (s, 6H), 2.00 (s, 6H), 1.58-1.71 (m, 4H), 0.95 (t, J=7.4Hz, 6H).13C-NMR(100MHz,CDCl3)δ203.4,168.7,167.9,154.9,149.9,143.8,127.5,123.2, 121.9,62.7,45.9,21.2,20.7,20.6,17.0,13.8,9.9.HRMS calcd for C33H40O12[M+H]+: 629.25925；found:629.25958.
35 1- of embodiment (3- (3- bytyry -2,6- dihydroxy -4- methoxyl group -5- methylbenzyl) -2,4- dihydroxy -5- Methyl -6- (2- propine -1- oxygroup) phenyl) butane -1- ketone
Referring to the synthetic method of embodiment 1, title compound is obtained by intermediate 6 and intermediate 27, faint yellow solid, is received Rate: 41%, mp98-100 DEG C,1H-NMR(300MHz,CDCl3)δ15.57(s,1H),15.38(s,1H),9.60(s,1H), 9.51 (s, 1H), 4.48 (d, J=2.4Hz, 2H), 3.86 (s, 2H), 3.71 (s, 3H), 3.16 (t, J=7.2Hz, 2H), 3.07 (t, J=7.5Hz, 2H), 2.53 (t, J=2.4Hz, 1H), 2.11 (s, 3H), 2.10 (s, 3H), 1.69-1.76 (m, 4H), 0.98 (t, J=7.2Hz, 6H)13C-NMR(75MHz,CDCl3)δ207.2,206.9,161.7,161.5,160.2,159.6, 159.2,157.2,112.3,112.1,109.7,109.0,108.7,107.8,61.5,61.4,44.9,44.2,18.1, 16.3,13.9,13.8,9.4,9.1.HRMS calcd for C27H33O8[M+H]+:485.21699；found:485.21707.
36 1 ' 1- of embodiment (di-2-ethylhexylphosphine oxide (4,6- dihydroxy -3- methyl -2- (2- propine -1- oxygroup) Asia -5,1- benzene Base)) bis- (butane -1- ketone)
Referring to the synthetic method of embodiment 1, title compound is obtained by intermediate 27, faint yellow solid, yield: 41%, Mp 184-185 DEG C,1H-NMR(300MHz,CDCl3) δ 15.40 (s, 2H), 9.56 (s, 2H), 4.48 (d, J=2.4Hz, 4H), 3.86 (s, 2H), 3.15 (t, J=7.2Hz, 2H), 3.07 (t, J=6.9Hz, 4H), 2.52 (t, J=2.4Hz, 2H), 2.14 (s, 6H), 1.69-1.76 (m, 4H), 0.98 (t, J=7.5Hz, 6H)13C-NMR(100MHz,CDCl3)δ207.3,161.5, 159.2,157.3,112.4,109.7,108.7,61.4,44.9,18.2,16.5,13.8,9.5.HRMS calcd for C29H33O8[M+H]+:509.21699；found:509.21759.
37 1- of embodiment (3- (3- bytyry -2,6- dihydroxy -4- methoxyl group -5- methylbenzyl) -2,4,6- trihydroxy Phenyl) -2- methybutane -1- ketone
Referring to the synthetic method of intermediate 3, intermediate 41 is obtained using phloroglucin as starting material, buff grease, Yield: 76%,1H-NMR(400MHz,DMSO-d6)δ12.23(s,2H),10.30(s,1H),5.79(s,2H),3.70-3.79 (m, 1H), 1.63-1.78 (m, 1H), 1.23-1.37 (m, 1H), 1.04 (d, J=6.6Hz, 3H), 0.83 (t, J=7.4Hz, 3H)。
Referring to the synthetic method of embodiment 1, title compound is obtained by intermediate 6 and intermediate 41, is brown solid, is received Rate: 96-98 DEG C of 41%, mp,1H-NMR(400MHz,CDCl3)δ15.47(s,1H),9.49(s,1H),9.34(s,1H),5.89 (s, 1H), 3.72-3.85 (m, 1H), 3.80 (s, 2H), 3.71 (s, 3H), 3.07 (t, J=7.3Hz, 2H), 2.11 (s, 3H), 1.80-1.89 (m, 1H), 1.65-1.78 (m, 2H), 1.33-1.46 (m, 1H), 0.98 (t, J=7.4Hz, 3H), 0.92 (t, J =7.4Hz, 4H)13C-NMR(100MHz,CDCl3)δ210.9,207.1,163.3,162.6,161.9,160.4,159.7, 158.8,112.3,109.7,108.0,106.6,103.8,96.9,61.7,45.9,44.4,27.0,18.4,16.7,16.1, 14.1,12.1,9.3.HRMS calcd for C24H31O8[M+H]+:447.20134；found:447.20108.
38 1- of embodiment (3- (3- bytyry -2,6- dihydroxy -4- methoxy-benzyl) -2,4,6- trihydroxy -5- methyl Phenyl) -2- methybutane -1- ketone
2,4,6- trihydroxybutyrophenones (42)
Referring to the synthetic method of intermediate 3, intermediate 42 is obtained by starting material of phloroglucin, yellow oil is received Rate: 81%,1H-NMR(400MHz,Acetone-d6) δ 11.69 (s, 2H), 9.12 (s, 1H), 5.92 (s, 2H), 3.04 (t, J= 7.3Hz, 2H), 1.64-1.73 (m, 2H), 0.95 (t, J=7.4Hz, 3H).
2,4- dimethoxy methoxyl group -6- hydroxyphenyl butanones (43)
Intermediate 43 is obtained referring to the synthetic method of intermediate 4, colorless oil, yield: 88%,1H-NMR(400MHz, CDCl3)δ13.77(s,1H),6.27(s,1H),6.25(s,1H),5.25(s,2H),5.17(s,2H),3.53(s,3H), 3.47 (s, 3H), 3.01 (t, J=7.3Hz, 2H), 1.67-1.76 (m, 2H), 0.99 (t, J=7.4Hz, 3H).
2,4- dimethoxy methoxyl group -6- methoxybenzene butanone (44)
Intermediate 44 is obtained referring to the synthetic method of intermediate 5, colorless oil, yield: 79%,1H-NMR(400MHz, CDCl3)δ6.44(s,1H),6.30(s,1H),5.14(s,2H),5.10(s,2H),3.75(s,3H),3.47(s,3H),3.43 (s, 3H), 2.70 (t, J=7.4Hz, 2H), 1.63-1.73 (m, 2H), 0.95 (t, J=7.4Hz, 3H).
2- methoxyl group -4,6- dihydroxy benzenes butanone (45)
Intermediate 45 is obtained referring to the synthetic method of intermediate 6, yellow solid, yield: 91%,1H-NMR(400MHz, Acetone-d6)δ13.96(s,1H),9.30(s,1H),6.03(s,1H),5.95(s,1H),3.90(s,3H),2.96(t,J =7.3Hz, 2H), 1.61-1.70 (m, 2H), 0.96 (t, J=7.3Hz, 3H).
Referring to the synthetic method of embodiment 1, title compound is obtained by intermediate 7 and intermediate 45, yellow solid, is received Rate: 147-149 DEG C of 52%, mp,1H-NMR(400MHz,CDCl3)δ16.29(s,1H),15.61(s,1H),9.44(s,1H), 9.36 (s, 1H), 6.03 (s, 1H), 3.83 (s, 3H), 3.79 (s, 2H), 2.97 (t, J=7.3Hz, 2H), 2.08 (s, 3H), 1.78-1.90 (m, 1H), 1.63-1.75 (m, 2H), 1.36-1.47 (m, 1H), 1.17 (d, J=6.7Hz, 3H), 0.99 (t, J =7.4Hz, 3H), 0.92 (t, J=7.3Hz, 3H)13C-NMR(100MHz,CDCl3)δ211.1,206.6,163.4,163.3, 162.2,160.4,160.4,106.7,106.4,106.4,104.9,103.8,102.7,92.7,55.8,46.0,45.9, 18.3,16.9,15.9,14.2,12.1,7.7.HRMS calcd for C24H31O8[M+H]+:447.20134；found: 447.20114。
Embodiment 39 1,1 '-(di-2-ethylhexylphosphine oxide (2,4- dihydroxy -6- methoxyl group -3,1- phenylene)) bis- (butane -1- ketone)
Referring to the synthetic method of embodiment 1, title compound is obtained by intermediate 45, yellow solid, yield: 28%, mp 205-207 DEG C,1H-NMR(400MHz,CDCl3)δ16.27(s,2H),9.39(s,2H),6.03(s,2H),3.83(s,6H), 3.77 (s, 2H), 2.97 (t, J=7.3Hz, 4H), 1.64-1.73 (m, 4H), 0.98 (t, J=7.3Hz, 6H)13C-NMR (100MHz,CDCl3)δ206.6,163.4,163.2,162.2,106.7,104.9,92.7,55.8,45.9,18.3,15.6, 14.2.HRMS calcd for C23H28O8[M+H]+:433.18569；found:433.18533.
40 1- of embodiment (3- (1- (3- bytyry 2,6- dihydroxy -4- methoxyl group -5- aminomethyl phenyl) ethyl) -2,4,6- Trihydroxy -5- aminomethyl phenyl) -2- methybutane -1- ketone
Intermediate 6 (0.1mmol), intermediate 7 (0.1mmol) are dissolved in 3mL DCM, are added TsCl (0.1mmol), acetaldehyde water Solution 10 drips, 1 medicine spoon of anhydrous sodium sulfate, and flow back 8h, filters, and is concentrated under reduced pressure, C18Silica gel column chromatography (MeOH/H2O=95:5 after) Title compound, yellow solid, yield: 88-90 DEG C of 20%, mp,1H-NMR(400MHz,CDCl3)δ16.09(s,1H), 15.72 (s, 1H), 9.68 (s, 2H), 4.89 (q, J=7.3Hz, 1H), 3.74-3.82 (m, 1H), 3.71 (s, 3H), 3.07 (t, J=7.3Hz, 2H), 2.10 (s, 3H), 2.08 (s, 3H), 1.81-1.88 (m, 1H), 1.79 (d, J=7.4Hz, 3H), 1.68- 1.78 (m, 1H), 1.17 (d, J=6.7Hz, 3H), 0.98 (t, J=7.4Hz, 3H), 0.92 (t, J=7.4Hz, 3H)13C-NMR (150MHz,CDCl3)δ211.1,207.1,162.0,160.6,160.0,155.8,113.5,112.5,110.0,107.8, 103.5,102.2,61.5,45.9,44.3,26.9,24.8,18.3,17.0,16.8,16.7,13.9,12.0,9.2, 7.5.HRMS calcd for C26H34O8[M+H]+:475.23264；found:475.23279.
41 1- of embodiment (3- ((3- bytyry -2,6- dihydroxy -4- methoxyl group -5- aminomethyl phenyl) (phenyl) methyl) - 2,4,6- trihydroxy -5- aminomethyl phenyl) -2- methybutane -1- ketone
Intermediate 6 (0.1mmol), intermediate 7 (0.1mmol) are dissolved in 3mL DCM, are added TsCl (0.1mmol), benzaldehyde (1mmol), flow back 8h after, filter, be concentrated under reduced pressure, C18Silica gel column chromatography (MeOH/H2O=95:5 title compound is obtained after), it is yellow Color solid, yield: 95-97 DEG C of 29%, mp,1H-NMR(400MHz,CDCl3)δ15.67(s,1H),9.43(s,2H),7.15- 7.29 (m, 3H), 7.09 (d, J=7.6Hz, 2H), 6.27 (s, 1H), 3.73-3.87 (m, 1H), 3.76 (s, 3H), 3.09 (t, J =7.2Hz, 2H), 2.14 (s, 3H), 2.11 (s, 3H), 1.80-1.89 (m, 1H), 1.66-1.78 (m, 2H), 1.33-1.50 (m, 1H), 1.18 (d, J=6.7,3H), 0.99 (t, J=7.4Hz, 3H), 0.86-0.96 (m, 3H)13C-NMR(100MHz, CDCl3)δ211.0,207.0,162.4,160.9,160.5,160.2,156.6,138.2,128.1,126.7,125.8, 112.7,111.0,108.0,107.4,103.8,102.6,61.5,45.9,44.4,34.3,26.9,18.2,16.7,13.9, 12.0,9.4,7.7.HRMS calcd for C31H37O8[M+H]+:537.24829；found:537.24835.
Embodiment 42 2- methyl -4- (2,4,6- trihydroxy benzyl) benzene -1,3,5- triphenol
Title compound is obtained referring to the synthetic method of intermediate 2, yellow solid, yield: 132-134 DEG C of 45%, mp,1H-NMR(400MHz,Acetone-d6)δ9.20(s,2H),8.92(s,1H),8.39(s,1H),8.06(s,1H),7.83(s, 1H),6.07(s,1H),6.02(s,2H),3.71(s,2H),1.98(s,3H).13C-NMR(100MHz,Acetone-d6)δ 158.0,156.3,155.5,155.3,152.9,106.7,106.6,104.4,96.4,95.8,17.4,8.6.HRMS calcd for C14H15O6[M+H]+:279.08631；found:279.08612.
43 8- of embodiment (3- bytyry -2,6- dihydroxy -4- methoxyl group -5- aminomethyl phenyl) -2- ethyl -5,7- dihydroxy Base -2,6- dimethylchroman -4- ketone
3- methyl -2- pentenoic acid ethyl ester (46)
At 0 DEG C, phosphonoacetate (50mmol) is added dropwise into THF (50mL) solution of NaH (50mmo), 1h is stirred, is then slowly added dropwise into 2- butanone (50mmol), 3h is stirred at room temperature, the NH of saturation is added4Cl solution quenching reaction, second Acetoacetic ester extraction, saturated common salt washing, anhydrous sodium sulfate is dry, is concentrated under reduced pressure, obtains intermediate 46, light yellow oil.Crude product It is directly used in and reacts in next step.
3- methyl -2- penetenoic acid (47)
The KOH solution (30mL, 60mmol) of 2N is added into methanol (30mL) solution of intermediate 46, flow back 20hs, subtracts Pressure is concentrated into 1/5 volume, is cooled to 0 DEG C, the dilute hydrochloric acid of 1N adjusts pH to 2, and ethyl acetate extraction, saturated common salt is washed, anhydrous Sodium sulphate dries, filters, and is concentrated under reduced pressure, and intermediate 47, yellow oil are obtained after silica gel column chromatography (PE/EA=5:1), and two steps are received Rate 42.1%,1H-NMR(400MHz,Acetone-d6): (E/Z=2.7:1) .E isomer δ 5.67 (s, 1H), 2.18 (q, J= 7.6,2H), 2.14 (s, 3H), 1.06 (t, J=7.6,3H)；Zisomer δ 5.65 (s, 1H), 2.63 (q, J=7.6,2H), 1.89 (s, 3H), 1.04 (t, J=7.6,3H).
2- ethyl -5,7- dihydroxy -2,6- dimethylchroman -4- ketone (48a) and 2- ethyl -5,7- dihydroxy -2,8- two Methyl chroman-4-on (48a ')
At room temperature, boron trifluoride ether 10mL, mixing are added into intermediate 2 (4mmol) and 47 (4.4mmol) mixtures Liquid is heated to 70 DEG C of reaction 2h, cooling, pours into ice water, and ethyl acetate extraction, anhydrous sodium sulfate is dry, is concentrated under reduced pressure, silica gel Column chromatograph (PE/DCM=5:1) 48a, yellow solid, yield 52%,1H-NMR(300MHz,DMSO-d6)δ12.34(s,1H), 10.66 (s, 1H), 5.91 (s, 1H), 2.78 (d, J=17.1,1H), 2.67 (d, J=17.1,1H), 1.86 (s, 1H), 1.57- 1.80 (m, 2H), 1.30 (s, 3H), 0.88 (t, J=7.5,3H)；And 48a ', faint yellow solid, yield 25%,1H-NMR (300MHz,DMSO-d6) δ 12.02 (s, 1H), 10.67 (s, 1H), 5.92 (s, 1H), 2.77 (d, J=17.1,1H), 2.69 (d, J=17.1,1H), 1.86 (s, 1H), 1.56-1.81 (m, 2H), 1.32 (s, 3H), 0.90 (t, J=7.5,3H)
Referring to the synthetic method of embodiment 40, title compound is obtained by intermediate 6 and intermediate 48a, faint yellow solid, Yield 17.5%, mp125-127 DEG C,1H-NMR(300MHz,DMSO-d6)δ13.60(s,1H),12.33(s,1H),9.52(s, 1H), 3.77 (s, 2H), 3.63 (s, 3H), 3.00 (t, J=7.2,2H), 2.75 (d, J=17.1,1H), 2.52 (d, J= 17.1,1H),2.01(s,3H),1.93(s,3H),1.57-1.64(m,2H),1.43-1.55(m,2H),1.08(s,3H), 0.90 (t, J=7.2,3H), 0.72 (t, J=7.2,3H)；13C-NMR(125MHz,DMSO-d6)δ205.8,196.8,162.4, 160.8,160.7,158.8,158.4,156.2,110.6,109.5,107.8,106.4,102.5,101.2,80.8,61.6, 44.5,43.9,31.5,22.9,17.9,16.9,13.8,9.4,7.76,7.70；ESI-MS:calculated,472.53； found,472.93[M+H]+；HR-MS(ESI):calculated,473.2175,C26H33O8,[M+H]+；found, 473.2181[M+H]+。
44 8,8 '-di-2-ethylhexylphosphine oxide of embodiment (2- ethyl -5,7- dihydroxy -2,6- dimethylchroman -4- ketone)
Referring to the synthetic method of embodiment 40, title compound is obtained by intermediate 48a, faint yellow solid, yield 25.1%, mp:195-197 DEG C,1H-NMR(300MHz,DMSO-d6)δ12.30(s,2H),9.54(s,2H),3.71(s,2H), 2.72 (d, J=16.5Hz, 2H), 2.46 (d, J=17.7Hz, 2H), 1.95 (s, 6H), 1.37-1.55 (m, 4H), 1.03 (s, 3H),0.90(s,3H),0.68-0.79(m,6H)；13C-NMR(125MHz,DMSO-d6)δ196.53,196.48,162.6, 158.04,158.03,156.04,156.01,107.2,107.1,102.11,102.06,101.0,80.41,80.39, 44.36,44.29,31.8,31.2,22.9,22.5,17.0,7.60,7.57；ESI-MS:calculated,484.54； found,485.08[M+H]+；HR-MS(ESI):calculated,485.2175,C27H33O8,[M+H]+；found, 485.2174[M+H]+。
45 6- of embodiment (3- bytyry -2,6- dihydroxy -4- methoxyl group -5- aminomethyl phenyl) -2- ethyl -5,7- dihydroxy Base -2,8- dimethylchroman -4- ketone
Referring to the synthetic method of embodiment 40, title compound is obtained by intermediate 6 and intermediate 48a ', pale yellow colored solid Body, yield 15.3%, mp112-114 DEG C,1H-NMR(300MHz,CDCl3)δ15.47(s,1H),13.61(s,1H),9.49(s, 1H), 9.16 (s, 1H), 3.80 (s, 2H), 3.71 (s, 3H), 3.07 (t, J=7.2Hz, 2H), 2.72 (d, J=16.8Hz, 1H), 2.61 (d, J=17.1Hz, 1H), 2.11 (s, 3H), 1.99 (s, 3H), 1.57-1.88 (m, 4H), 1.37 (s, 3H), 0.93-1.01 (q, J=7.5Hz, 6H)；13C-NMR(125MHz,CDCl3)δ206.9,197.0,163.1,161.4,160.2, 159.5,157.2,156.5,112.1,109.3,107.9,105.9,105.1,101.4,80.8,61.6,45.9,44.3, 32.1,23.6,18.2,15.6,13.9,9.1,7.9；ESI-MS:calculated,472.53；found,472.95[M+H]+； HR-MS(ESI):calculated,473.2175,C26H33O8,[M+H]+；found,473.2183[M+H]+。
46 6,6 '-di-2-ethylhexylphosphine oxide of embodiment (2- ethyl -5,7- dihydroxy -2,8- dimethylchroman -4- ketone)
Referring to the synthetic method of embodiment 40, title compound is obtained by intermediate 48a ', yellow solid, yield 213-215 DEG C of 39.9%, mp,1H-NMR(300MHz,DMSO-d6)δ12.71(s,2H),9.50(br,2H),3.72(s,2H), 2.78 (d, J=17.1Hz, 2H), 2.70 (d, J=17.7Hz, 2H), 1.91 (s, 6H), 1.51-1.81 (m, 4H), 1.30 (s, 6H), 0.89 (t, J=7.5Hz, 6H)；13C-NMR(125MHz,DMSO-d6)δ196.9,162.4,158.0,155.9,105.7, 102.9,101.0,80.5,45.4,31.1,23.0,15.0,8.0,7.6；ESI-MS:calculated,484.54；found, 484.98[M+H]+；HR-MS(ESI):calculated,485.2175,C27H33O8,[M+H]+；found,485.2182[M+H]+。
47 8- of embodiment (3- bytyry -2,6- dihydroxy -4- methoxyl group -5- aminomethyl phenyl) chloro- 2- ethyl -5,7- of -6- Dihydroxy -2- methyl chroman-4-on
3- chloro- 2,4,6- trihydroxybenzoic acids (49)
At 0 DEG C, dropwise into anhydrous ether (50mL) solution of 2,4,6- trihydroxybenzoic acid monohydrates (20mmol) SO is added2Cl2(24mmol), is added dropwise, and 2h is stirred at room temperature, and reaction solution pours into ice water, and anhydrous sodium sulfate is dry, depressurizes dense Contract to obtain intermediate 49, faint yellow solid, yield 97.7%,1H-NMR(300MHz,DMSO-d6)δ10.74(br,4H),6.02(s, 1H)；ESI-MS:calculated,204.56；found,203.13[M-H]-。
2,4,6- trihydroxy chlorobenzenes (50)
Intermediate 49 (10mmol) is dissolved in 18mLN, and in accelerine, 150 DEG C of reaction 2h are cooling, by reaction solution The ice water solution of concentrated hydrochloric acid is poured into, ethyl acetate extraction, the hydrochloric acid solution washing of 6N, anhydrous sodium sulfate is dry, is concentrated under reduced pressure, silicon Plastic column chromatography (DCM/Methanol=80:1) intermediate 50, faint yellow solid, yield 86.7%,1H-NMR(300MHz, DMSO-d6)δ9.61(s,2H),9.16(s,2H),5.91(s,H)；ESI-MS:calculated,160.56；found, 159.02[M-H]-。
The chloro- 2- ethyl -5,7- dihydroxy -2- methyl chroman-4-on (51a) of 6- and the chloro- 2- ethyl -5,7- dihydroxy-of 8- 2- methyl chroman-4-on (51a ')
Intermediate 51a is obtained referring to the synthetic method of intermediate 48, faint yellow solid, yield 55%,1H-NMR (300MHz,DMSO-d6) δ 12.66 (s, 1H), 11.55 (s, 1H), 6.05 (s, 1H), 2.86 (d, J=17.1Hz, 1H), 2.74 (d, J=17.1Hz, 1H), 1.59-1.82 (m, 2H), 1.32 (s, 3H), 0.89 (t, J=7.5Hz, 3H)；ESI-MS: calculated,256.68；found,257.23[M+H]+；And 51a ', yellow solid, yield 17%,1H-NMR(400MHz, DMSO-d6) δ 12.02 (s, 1H), 11.50 (s, 1H), 6.06 (s, 1H), 2.86 (d, J=17.2Hz, 1H), 2.80 (d, J= 17.2Hz, 1H), 1.61-1.84 (m, 2H), 1.36 (s, 3H), 0.92 (t, J=7.2Hz, 3H)；ESI-MS:calculated, 256.68；found,257.23[M+H]+.
Referring to the synthetic method of embodiment 24, title compound is obtained by intermediate 34 and intermediate 51a, pale yellow colored solid Body, yield 21.8%, mp:116-118 DEG C,1H-NMR(300MHz,DMSO-d6)δ13.53(s,1H),12.66(s,1H),3.79 (s, 2H), 3.63 (s, 3H), 2.99 (t, J=7.2Hz, 2H), 2.79 (d, J=17.1Hz, 1H), 2.57 (d, J=17.1Hz, 1H), 2.00 (s, 3H), 1.37-1.64 (m, 4H), 1.04 (s, 3H), 0.89 (t, J=7.2Hz, 3H), 0.70 (t, J= 6.6Hz,3H)；13C-NMR(125MHz,DMSO-d6)δ205.5,196.6,161.1,160.7,158.6,156.6,155.9, 110.4,109.3,108.2,107.5,101.0,99.3,81.0,61.5,44.0,43.7,31.4,22.7,17.8,17.3, 13.7,9.2,7.5；ESI-MS:calculated,492.95；found,492.68[M+H]+；HR-MS(ESI): calculated,493.1629,C25H30ClO8,[M+H]+；found,493.1633[M+H]+。
48 6- of embodiment (3- bytyry -2,6- dihydroxy -4- methoxyl group -5- aminomethyl phenyl) chloro- 2- ethyl -5,7- of -8- Dihydroxy -2- methyl chroman-4-on
Referring to the synthetic method of embodiment 24, title compound is obtained by intermediate 34 and intermediate 51a ', yellow oily Object, yield 36.5%,1H-NMR(400MHz,Acetone-d6)δ15.69(s,1H),13.71(s,1H),9.30(br,2H), 3.87 (s, 2H), 3.79 (s, 3H), 3.16 (t, J=7.2Hz, 2H), 2.93 (d, J=17.2Hz, 1H), 2.85 (d, J= 17.6Hz, 1H), 2.09 (s, 1H), 1.89 (m, 1H), 1.68-1.79 (m, 3H), 1.44 (s, 3H), 0.99 (t, J=7.2Hz, 3H), 0.98 (t, J=7.2Hz, 3H)；13C-NMR(100MHz,Acetone-d6)δ207.2,197.3,161.0,160.6, 160.2,159.5,157.1,155.4,111.8,108.7,108.1,106.3,101.8,101.4,82.8,61.2,45.2, 44.0,31.4,22.6,17.7,15.3,13.2,8.5,7.1；ESI-MS:calculated,492.95；found,492.74[M +H]+；HR-MS(ESI):calculated,493.1629,C25H30ClO8,[M+H]+；found,493.1642[M+H]+。
49 8- of embodiment (3- bytyry -2,6- dihydroxy -4- methoxyl group -5- aminomethyl phenyl) bromo- 2- ethyl -5,7- of -6- Dihydroxy -2- methyl chroman-4-on
2,4,6- trihydroxy bromobenzenes (52) and 2,4,6- trihydroxy -1,3- dibromobenzenes (53)
Under room temperature, ammonium bromide (22mmol) and excessively one are added into methanol (100mL) solution of phloroglucin (20mmol) Potassium acid sulfate complex salt (22mmol) reacts 30min, filters, and is concentrated under reduced pressure, silica gel column chromatography (DCM/methanol=50:1) Obtain intermediate 52, white solid, yield 66%,1H-NMR(300MHz,DMSO-d6)δ9.69(s,2H),9.20(s,1H), 5.92(s,2H)；ESI-MS:calculated,205.01；found,202.91[M-H]-；And intermediate 53, yellow solid are received Rate 7.0%,1H-NMR(300MHz,DMSO-d6)δ10.07(s,2H),9.20(s,1H),6.27(s,1H)；ESI-MS: calculated,283.90；found,282.96[M-H]-。
The bromo- 2- ethyl -5,7- dihydroxy -2- methyl chroman-4-on (54a) of 6- and the bromo- 2- ethyl -5,7- dihydroxy-of 8- 2- methyl chroman-4-on (54a ')
Intermediate 54a is obtained referring to the synthetic method of intermediate 48, yellow solid, yield 48%,1H-NMR(400MHz, DMSO-d6) δ 12.80 (s, 1H), 11.58 (s, 1H), 6.06 (s, 1H), 2.86 (d, J=17.6Hz, 1H), 2.75 (d, J= 17.6Hz 1H), 1.61-1.82 (m, 2H), 1.32 (s, 3H), 0.89 (t, J=7.2Hz, 3H)；ESI-MS:calculated, 301.00；found,299.36[M-H]-；And 54a ', yellow solid, yield 19%,1H-NMR(400MHz,DMSO-d6)δ 12.07 (s, 1H), 11.54 (s, 1H), 6.07 (s, 1H), 2.86 (d, J=17.2Hz, 1H), 2.80 (d, J=17.2Hz, 1H), 1.59-1.84 (m, 2H), 1.35 (s, 3H), 0.93 (t, J=7.6Hz, 3H)；ESI-MS:calculated,301.00； found,299.36[M-H]-.
Referring to the synthetic method of embodiment 24, title compound is obtained by intermediate 34 and intermediate 54a, yellow solid, Yield 24.2%, mp:108-110 DEG C,1H-NMR(400MHz,Acetone-d6)δ13.14(s,1H),3.87(s,2H),3.70 (s, 3H), 3.05 (t, J=7.2Hz, 2H), 2.74 (d, J=16.8Hz, 1H), 2.57 (d, J=16.8Hz, 1H), 2.04 (s, 3H), 1.77-1.93 (m, 2H), 1.69 (m, 2H), 1.41 (s, 3H), 0.99 (t, J=7.6Hz, 3H), 0.95 (t, J= 7.2Hz,3H)；13C-NMR(100MHz,Acetone-d6)δ194.7,164.7,161.8,161.4,160.3,160.1, 157.4,111.4,109.3,108.5,100.5,93.0,82.1,61.8,45.5,45.0,32.9,23.7,19.0,18.2, 14.2,9.5,8.3；ESI-MS:calculated,537.40；found,536.54[M+H]+.HR-MS(ESI): calculated,537.1124,C25H30BrO8,[M+H]+；found,537.1134,[M+H]+。
50 6- of embodiment (3- bytyry -2,6- dihydroxy -4- methoxyl group -5- aminomethyl phenyl) bromo- 2- ethyl -5,7- of -8- Dihydroxy -2- methyl chroman-4-on
Referring to the synthetic method of embodiment 24, title compound is obtained by intermediate 34 and intermediate 54a ', yellow oily Object, yield 18.7%,1H-NMR(400MHz,Acetone-d6)δ15.73(s,1H),13.80(s,1H),9.88(br,H), 8.95 (br, H), 3.88 (s, 2H), 3.80 (s, 3H), 3.16 (t, J=7.2Hz, 2H), 2.93 (d, J=17.6Hz, 1H), 2.85 (d, J=17.6Hz, 1H), 2.09 (s, 3H), 1.90 (m, 1H), 1.68-1.78 (m, 3H), 1.44 (s, 3H), 0.96- 1.02(m,6H)；13C-NMR(100MHz,Acetone-d6)δ208.2,198.3,162.0,161.9,161.6,160.3, 158.8,157.4,112.8,109.6,109.0,107.2,102.9,91.6,83.7,62.1,46.2,44.9,32.3,23.4, 18.6,16.4,14.1,9.4,8.1；ESI-MS:calculated,537.40；found,537.20[M+H]+；HR-MS (ESI):calculated,537.1124,C25H30BrO8,[M+H]+；found,537.1137,[M+H]+.
51 8- of embodiment (3- bytyry -2,6- dihydroxy -4- methoxyl group -5- aminomethyl phenyl) -6- methyl formate -2- second Base -5,7- dihydroxy -2- methyl chroman-4-on
2,4,6- trihydroxybenzoates (55)
Under room temperature, to 2,4,6- trihydroxybenzoic acid monohydrates (20mmol) and K2CO3The acetone (50mL) of (20mmol) Dimethyl suflfate (22mmol) is added in solution, stirs 48h, filters, is concentrated under reduced pressure, solid is dissolved in ethyl acetate, with 5% it is dilute The NaHCO of hydrochloric acid, saturation3Solution, saturated salt solution successively wash, and organic phase is dry with anhydrous sodium sulfate, are concentrated under reduced pressure, silica gel The intermediate 55 of column chromatography (DCM/MeOH=25:1), yellow solid, yield 97.7%,1H-NMR(300MHz,DMSO-d6)δ 10.38(s,2H),10.16(s,1H),5.80(s,1H),3.80(s,1H)；ESI-MS:calculated,184.15；found, 182.92[M-H]-。
6- methyl formate -2- ethyl -5,7- dihydroxy -2- methyl chroman-4-on (56a) and 8- methyl formate -2- ethyl - 5,7- dihydroxy -2- methyl chroman-4-on (56a ')
Intermediate 56a is obtained referring to the synthetic method of intermediate 48, white solid, yield 39%,1H-NMR(300MHz, DMSO-d6) δ 12.94 (s, 1H), 11.63 (s, 1H), 5.94 (s, 1H), 3.77 (s, 3H), 2.89 (d, J=17.4Hz, 1H), 2.76 (d, J=17.4Hz, 1H), 1.59-1.82 (m, 2H), 1.33 (s, 3H), 0.90 (t, J=7.5Hz, 3H)；ESI-MS: calculated,280.27；found,280.93[M+H]+；And intermediate 56a ', yellow solid, yield 32%,1H-NMR (300MHz,DMSO-d6) δ 12.26 (s, 1H), 11.46 (s, 1H), 5.95 (s, 1H), 3.75 (s, 3H), 2.86 (d, J= 17.4Hz, 1H), 2.77 (d, J=17.4Hz, 1H), 1.52-1.85 (m, 2H), 1.31 (s, 3H), 0.90 (t, J=7.5Hz, 3H)；ESI-MS:calculated,280.27；found,280.93[M+H]+.
Referring to the synthetic method of embodiment 24, title compound is obtained by intermediate 34 and intermediate 56a, yellow solid, Yield 22.8%, mp:154-156 DEG C；1H-NMR(400MHz,CDCl3)δ13.94(s,1H),13.89(s,1H),13.83(s, 1H), 7.83 (s, 1H), 4.00 (s, 3H), 3.90 (dd, J=15.2Hz, 1H), 3.68 (s, 3H), 3.05 (t, J=7.2Hz, 2H), 2.77 (d, J=16.8Hz, 1H), 2.60 (d, J=17.2Hz, 1H), 2.07 (s, 3H), 1.68-1.77 (m, 4H), 1.35 (s, 3H), 0.97 (t, J=7.2Hz, 3H), 0.85 (t, J=7.2Hz, 3H)；13C-NMR(150MHz,CDCl3)δ206.4, 197.1,171.9,166.8,165.2,163.0,161.7,160.7,159.7,110.1,108.8,108.3,106.3, 101.6,95.1,82.6,61.6,52.9,45.0,44.6,32.0,23.9,18.4,15.2,14.0,8.9,7.8；ESI-MS: calculated,516.54；found,516.83[M+H]+；HR-MS(ESI):calculated,517.2074,C27H33O10, [M+H]+；found,517.2077,[M+H]+。
52 6- of embodiment (3- bytyry -2,6- dihydroxy -4- methoxyl group -5- aminomethyl phenyl) -8- methyl formate -2- second Base -5,7- dihydroxy -2- methyl chroman-4-on
Referring to the synthetic method of embodiment 24, title compound is obtained by intermediate 34 and intermediate 56a ', yellow solid, Yield 44.5%, mp:130-132 DEG C,1H-NMR(400MHz,CDCl3)δ14.37(s,1H),13.65(s,1H),12.34(s, 1H), 8.27 (s, 1H), 3.91 (s, 3H), 3.87 (s, 2H), 3.70 (s, 3H), 3.05 (t, J=7.2Hz, 2H), 2.77 (d, J =16.8Hz, 1H), 2.63 (d, J=17.2Hz, 1H), 2.09 (s, 3H), 1.88 (m, 1H), 1.63-1.77 (m, 3H), 1.39 (s, 3H), 1.00 (t, J=7.2Hz, 3H), 0.97 (t, J=7.6Hz, 3H)；13C-NMR(150MHz,CDCl3)δ206.5, 196.6,169.5,166.0,162.8,160.8,160.7,160.5,159.8,110.8,108.8,108.5,106.3, 101.3,99.0,82.7,61.6,52.5,45.8,44.5,32.5,22.8,18.3,15.1,14.0,9.0,7.6；ESI-MS: calculated,516.54；found,517.25[M+H]+；HR-MS(ESI):calculated,517.2074,C27H33O10, [M+H]+；found,517.2081,[M+H]+。
53 6,6 '-di-2-ethylhexylphosphine oxide of embodiment (2- ethyl -5,7- dihydroxy -2,8- dicarboxylic acid methyl ester chroman-4-on)
Referring to the synthetic method of embodiment 24, title compound is obtained by intermediate 56a ', yellow solid, yield 14.7%, mp:212-214 DEG C,1H-NMR(400MHz,CDCl3)δ13.03(s,2H),12.80(s,2H),3.89(s,6H), 3.88 (s, 2H), 2.77 (d, J=16.8Hz, 1H), 2.59 (d, J=17.2Hz, 1H), 1.89 (m, 2H), 1.70 (m, 2H), 1.39 (s, 6H), 1.02 (t, J=7.2Hz, 6H)；13C-NMR(150MHz,CDCl3)δ196.3,171.6,168.6,165.1, 161.8,107.0,101.3,95.2,82.3,52.2,45.9,32.8,22.6,15.0,7.7；ESI-MS:calculated, 572.56；found,572.88[M+H]+；HR-MS(ESI):calculated,573.1972,C29H33O12,[M+H]+；found, 573.1976,[M+H]+。
54 8- of embodiment (3- bytyry -2,6- dihydroxy -4- methoxyl group -5- aminomethyl phenyl) chloro- 2,2- diethyl-of -6- 5,7- dihydroxy chroman-4-on
3- ethyl -2- penetenoic acid (57)
Intermediate 57 is obtained referring to the synthetic method of intermediate 47, yield 52.7%,1H-NMR(300MHz,Acetone- d6) (m, the 6H) of δ 5.62 (s, 1H), 2.63 (q, J=7.5Hz, 2H), 2.22 (m, 2H), 1.05
The chloro- 2,2- diethyl -5,7- dihydroxy chroman-4-on (58a) of 6- and the chloro- 2,2- diethyl -5,7- dihydroxy of 8- Chroman-4-on (58a ')
Intermediate 58a is obtained referring to the synthetic method of intermediate 48, yellow solid, yield 32%,1H-NMR(300MHz, DMSO-d6)δ12.64(s,1H),11.55(s,1H),6.05(s,1H),2.79(s,2H),1.59-1.80(m,4H),0.84 (t, J=7.5Hz, 6H)；ESI-MS:calculated,270.71；found,269.41[M-H]-；And 58a ', yellow solid, Yield 42%,1H-NMR(400MHz,DMSO-d6)δ12.02(s,1H),11.50(s,1H),6.06(s,1H),2.79(s,2H), 1.59-1.78 (m, 4H), 0.82 (t, J=7.5Hz, 6H)；ESI-MS:calculated,270.71；found,269.41[M- H]-。
Referring to the synthetic method of embodiment 24, title compound is obtained by intermediate 34 and intermediate 58a, yellow solid, Yield 23.7%, mp:155-157 DEG C,1H-NMR(300MHz,Acetone-d6)δ3.93(s,2H),3.77(s,3H),3.13 (t, J=7.2Hz, 2H), 2.84 (s, 2H), 2.10 (s, 3H), 1.82-1.99 (m, 4H), 1.71 (m, 2H), 0.92-0.99 (m, 9H)；13C-NMR(150MHz,Acetone-d6)δ207.6,197.5,161.7,161.2,158.1,156.5,111.6, 109.8,109.0,107.4,86.7,62.1,45.0,43.8,43.7,28.9,18.7,17.1,14.1,9.3,8.0；ESI- MS:calculated,506.97；found,507.19[M+H]+；HR-MS(ESI):calculated,507.1786, C26H32ClO8,[M+H]+；found,507.1787,[M+H]+。
55 6- of embodiment (3- bytyry -2,6- dihydroxy -4- methoxyl group -5- aminomethyl phenyl) chloro- 2,2- diethyl-of -8- 5,7- dihydroxy chroman-4-on
Referring to the synthetic method of embodiment 24, title compound is obtained by intermediate 34 and intermediate 58a ', yellow solid, Yield 25.0%, mp:115-117 DEG C；1H-NMR(300MHz,Acetone-d6)δ3.87(s,2H),3.79(s,3H),3.15 (t, J=7.2Hz, 2H), 2.88 (s, 3H), 2.09 (s, 3H), 1.66-1.90 (m, 6H), 0.92-1.00 (m, 9H)；13C-NMR (150MHz,Acetone-d6)δ208.0,198.2,161.7,161.5,161.1,156.1,112.7,109.5,109.0, 107.1,102.7,102.2,85.9,62.1,44.9,43.9,28.8,18.6,16.2,14.1,9.3,7.8；ESI-MS: calculated,506.97；found,507.15[M+H]+；HR-MS(ESI):calculated,507.1786,C26H32ClO8, [M+H]+；found,507.1789,[M+H]+。
Embodiment 568- (3- bytyry -2,6- dihydroxy -4- methoxyl group -5- aminomethyl phenyl) chloro- 2,2- dimethyl-of -6- 5,7- dihydroxy chroman-4-on
The chloro- 2,2- dimethyl -5,7- dihydroxy chroman-4-on (59a) of 6- and the chloro- 2,2- dimethyl -5,7- dihydroxy of 8- Chroman-4-on (59a ')
Intermediate 59a is obtained referring to the synthetic method of intermediate 48, yellow solid, yield 54%,1H-NMR(300MHz, DMSO-d6)δ12.68(s,1H),11.55(s,1H),6.04(s,1H),2.82(s,2H),1.38(s,6H)；ESI-MS: calculated,242.66；found,241.49[M-H]-；And 59a ', white solid, yield 25%,1H-NMR(300MHz, DMSO-d6)δ12.05(s,1H),11.51(s,1H),6.06(s,1H),2.85(s,2H),1.42(s,6H)；ESI-MS: calculated,242.66；found,241.49[M-H]-。
Referring to the synthetic method of embodiment 24, title compound is obtained by intermediate 34 and intermediate 59a, yellow solid, Yield 19.3%, mp:193-195 DEG C；1H-NMR(300MHz,Acetone-d6)δ3.90(s,2H),3.76(s,3H),3.11 (t, J=7.2Hz, 2H), 2.84 (s, 2H), 2.10 (s, 3H), 1.70 (m, 2H), 1.53 (s, 6H), 0.96 (t, J=7.5Hz, 3H)；13C-NMR(150MHz,Acetone-d6)δ201.7,156.8,154.2,152.4,109.1,107.5,106.3, 105.4,79.9,61.0,47.13,47.07,44.5,26.5,19.1,17.7,14.6,10.0；ESI-MS:calculated, 478.92；found,479.23[M+H]+；HR-MS(ESI):calculated,479.1473,C24H28ClO8,[M+H]+； found,479.1471,[M+H]+。
57 6- of embodiment (3- bytyry -2,6- dihydroxy -4- methoxyl group -5- aminomethyl phenyl) chloro- 2,2- dimethyl-of -8- 5,7- dihydroxy chroman-4-on
Referring to the synthetic method of embodiment 24, title compound is obtained by intermediate 34 and intermediate 59a ', yellow solid, Yield 33.4%, mp:191-193 DEG C；1H-NMR(300MHz,Acetone-d6)δ3.87(s,2H),3.79(s,3H),3.15 (t, J=7.2Hz, 2H), 2.89 (s, 2H), 2.09 (s, 3H), 1.72 (m, 2H), 1.50 (s, 6H), 0.97 (t, J=7.2Hz, 3H)；13C-NMR(150MHz,Acetone-d6)δ207.1,197.0,160.9,160.5,155.5,111.7,108.7, 106.2,101.5,101.4,80.5,61.2,46.4,44.1,25.8,17.7,15.4,13.2,8.4；ESI-MS: calculated,478.92；found,479.23[M+H]+；HR-MS(ESI):calculated,479.1473,C24H28ClO8, [M+H]+；found,479.1478,[M+H]+。
58 8- of embodiment (3- bytyry -2,6- dihydroxy -4- methoxyl group -5- aminomethyl phenyl) chloro- 2- propyl -5,7- of -6- Dihydroxy -2- methyl chroman-4-on
3- methyl -2- hexenoic acid (60)
Intermediate 60 is obtained referring to the synthetic method of intermediate 47, yield 72.8%,1H-NMR(400MHz,Acetone- d6) (E/Z=3:2) .E isomer δ 10.32 (s, 1H), 5.68 (s, 1H), 2.15 (t, J=7.6Hz, 2H), 2.13 (s, 3H), 1.51 (m, 2H), 0.91 (t, J=7.2Hz, 3H)；Z isomer δ 10.32 (s, 1H), 5.68 (s, 1H), 2.63 (t, J= 7.6Hz, 2H), 1.89 (s, 3H), 1.51 (m, 2H), 0.92 (t, J=7.2Hz, 3H)；ESI-MS:calculated,128.17； found,127.12[M-H]-。
The chloro- 2- propyl -5,7- dihydroxy -2- methyl chroman-4-on (61a) of 6- and the chloro- 2- propyl -5,7- dihydroxy-of 8- 2- methyl chroman-4-on (61a ')
Intermediate 61a is obtained referring to the synthetic method of intermediate 48, yellow solid, yield 34%,1H-NMR(400MHz, CDCl3) δ 12.61 (s, 1H), 6.31 (s, 1H), 6.11 (s, 1H), 2.77 (d, J=16.8Hz, 1H), 2.63 (d, J= 16.8Hz, 1H), 1.60-1.79 (m, 2H), 1.43 (m, 2H), 1.40 (s, 3H), 0.94 (t, J=7.2Hz, 3H)；And intermediate 61a ', yellow solid, yield 27%,1H-NMR(400MHz,CDCl3) δ 11.92 (s, 1H), 6.18 (s, 2H), 2.78 (d, J= 16.8Hz, 1H), 2.66 (d, J=17.2Hz, 1H), 1.63-1.85 (m, 2H), 1.42-1.54 (m, 2H), 1.45 (s, 3H), 0.95 (t, J=7.2Hz, 3H).
Referring to the synthetic method of embodiment 24, title compound is obtained by intermediate 34 and intermediate 61a, yellow solid, Yield 11.4%, mp:157-159 DEG C,1H-NMR(400MHz,Acetone-d6)δ12.71(s,1H),3.91(s,2H),3.78 (s, 3H), 3.13 (t, J=7.2Hz, 2H), 2.93 (d, J=17.2Hz, 1H), 2.77 (d, J=17.2Hz, 1H), 2.11 (s, 3H), 1.83 (m, 2H), 1.71 (m, 2H), 1.39-1.57 (m, 2H), 1.49 (s, 3H), 0.97 (t, J=7.2Hz, 3H), 0.94 (t, J=7.6Hz, 3H)；13C-NMR(100MHz,Acetone-d6)δ207.7,197.3,162.1,161.8,161.2, 161.1,158.6,156.4,111.8,110.0,108.9,107.6,102.6,101.9,84.1,62.1,46.2,45.0, 42.2,24.0,18.8,17.7,17.3,14.6,14.1,9.4；ESI-MS:calculated,506.97；found,507.04 [M+H]+；HR-MS(ESI):calculated,507.1780,C26H32ClO8,[M+H]+；found,507.1785,[M+H]+。
59 6- of embodiment (3- bytyry -2,6- dihydroxy -4- methoxyl group -5- aminomethyl phenyl) chloro- 2- propyl -5,7- of -8- Dihydroxy -2- methyl chroman-4-on
Referring to the synthetic method of embodiment 24, title compound is obtained by intermediate 34 and intermediate 61a ', yellow oily Object, yield 14.8%,1H-NMR(400MHz,Acetone-d6)δ15.68(br,1H),13.71(s,1H),3.86(s,2H), 3.79 (s, 3H), 3.16 (t, J=7.2Hz, 2H), 2.93 (d, J=17.2Hz, 1H), 2.84 (d, J=17.2Hz, 1H), 2.09 (s, 3H), 1.83 (m, 1H), 1.68-1.77 (m, 3H), 1.49 (m, 2H), 1.46 (s, 3H), 0.98 (t, J=7.2Hz, 3H), 0.91 (t, J=7.2Hz, 3H)；13C-NMR(100MHz,Acetone-d6)δ208.1,198.2,161.9,161.6,161.2, 160.4,158.0,156.3,112.8,109.6,109.0,107.2,102.7,102.3,83.5,62.1,46.4,44.9, 42.0,24.1,18.6,17.4,16.3,14.5,14.1,9.4；ESI-MS:calculated,506.97；found,507.27 [M+H]+；HR-MS(ESI):calculated,507.1780,C26H32ClO8,[M+H]+；found,507.1783,[M+H]+。
The chloro- 8- of 60 6- of embodiment (2,6- dihydroxy -4- methoxyl group -3- methyl -5- (2- methylbutyryl) phenyl) -2- Ethyl -5,7- dihydroxy -2- methyl chroman-4-on
Referring to the synthetic method of embodiment 24, title compound is obtained by intermediate 18 and intermediate 51a, yellow solid, Yield 12.4%, mp:157-159 DEG C；1H-NMR(400MHz,Acetone-d6)δ12.70(s,1H),3.92(s,2H),3.79 (m, 1H), 3.76 (s, 3H), 2.93 (d, J=17.2Hz, 1H), 2.78 (d, J=17.2Hz, 1H), 2.11 (s, 3H), 1.75- 1.96 (m, 3H), 1.48 (s, 3H), 1.40 (m, 1H), 1.16 (d, J=6.8Hz, 3H), 1.01 (t, J=7.2Hz, 3H), 0.89 (t, J=7.2Hz, 3H)；13C-NMR(100MHz,Acetone-d6)δ212.1,197.4,161.9,161.4,161.2, 161.0,158.6,156.4,111.9,110.1,108.5,107.6,102.7,101.9,84.5,62.7,45.9,45.8, 32.5,28.0,23.5,17.5,17.3,12.2,9.4,8.3；ESI-MS:calculated,506.97；found,507.12[M +H]+；HR-MS(ESI):calculated,507.1780,C26H32ClO8,[M+H]+；found,507.1784,[M+H]+。
The chloro- 8- of 61 6- of embodiment (2,6- dihydroxy -4- methoxyl group -3- methyl -5- (2- methylbutyryl) phenyl) -5, 7- dihydroxy -2- methyl-2-propyl chroman-4-on
Referring to the synthetic method of embodiment 24, title compound is obtained by intermediate 18 and intermediate 61a, yellow solid, Yield 12.7%, mp:114-116 DEG C；1H-NMR(400MHz,Acetone-d6)δ12.66(s,1H),3.92(s,2H),3.80 (m, 1H), 3.78 (s, 3H), 2.95 (d, J=17.2Hz, 1H), 2.80 (d, J=17.2Hz, 1H), 2.12 (s, 3H), 1.75- 1.89 (m, 3H), 1.37-1.58 (m, 3H), 1.66 (d, J=6.8Hz, 3H), 0.94 (t, J=7.2Hz, 3H), 0.90 (t, J= 7.2Hz,3H)；13C-NMR(100MHz,Acetone-d6)δ212.3,197.6,161.7,161.3,161.1,160.6, 158.5,156.4,112.0,109.9,108.5,107.4,102.9,101.8,84.4,62.7,46.2,45.9,42.1, 28.0,24.0,17.7,17.5,17.3,14.6,12.2,9.4；ESI-MS:calculated,521.00；found,521.50 [M+H]+；HR-MS(ESI):calculated,521.1937,C27H34ClO8,[M+H]+；found,521.1940,[M+H]+。
62 8- of embodiment (3- bytyry -2,6- dihydroxy -4- methoxyl group -5- aminomethyl phenyl) chloro- 3- ethyl -5,7- of -6- Dihydroxy chroman-4-on
2,4,6- trihydroxy -3- chlorobenzene butanone (62)
Intermediate 62 is obtained referring to the synthetic method of intermediate 3, yellow solid, yield 58%,1H-NMR(400MHz, Acetone-d6) δ 13.52 (s, 1H), 10.57 (s, 1H), 9.57 (s, 1H), 6.19 (s, 1H), 3.08 (t, J=7.2Hz, 2H), 3.08 (t, J=7.2Hz, 2H), 1.69 (m, 2H), 0.96 (t, J=7.2Hz, 3H).
Chloro- 2, the 4- dimethoxy methoxybenzene butanone (63) of 6- hydroxyl -3-
Intermediate 63 is obtained referring to the synthetic method of intermediate 4, yellow oil, yield 46%,1H-NMR(400MHz, CDCl3)δ12.98(s,1H),6.59(s,1H),5.27(s,2H),5.18(s,2H),3.57(s,3H),3.51(s,3H), 3.15 (t, J=7.2Hz, 2H), 1.71 (m, 2H), 0.97 (t, J=7.6Hz, 3H).
Chloro- 3- ethyl -5, the 7- dimethoxy methoxyl group chroman-4-on (64) of 6-
It in 50mL round-bottomed flask, is added raw material 63 (1.3553mmol), is dissolved in 25mL dehydrated alcohol, poly first is added Aldehyde (4.7435mmol) and diethylamine (13.553mmol), reaction solution are heated to reflux for 24 hours, are concentrated under reduced pressure, are dissolved in ethyl acetate, Washing, anhydrous sodium sulfate are dry, concentration, silica gel column chromatography (PE/EA=15:1) 64, yellow oil, yield 74%,1H- NMR(400MHz,Acetone-d6) δ 6.60 (s, 1H), 5.37 (s, 2H), 5.11 (dd, J=13.6Hz, 2H), 4.56 (dd, J =4.4Hz, J=11.2Hz, 1H), 4.33 (dd, J=8.0Hz, J=11.2Hz, 1H), 3.59 (s, 3H), 3.49 (s, 3H), 2.46-2.52 (m, 1H), 1.81 (m, 1H), 1.52 (m, 1H), 0.99 (t, J=7.6Hz, 3H).
Chloro- 3- ethyl -5, the 7- dihydroxy chroman-4-on (65) of 6-
Intermediate 65 is obtained referring to the synthetic method of intermediate 6, yellow solid, yield 63%,1H-NMR(400MHz, Acetone-d6) δ 12.86 (s, 1H), 9.90 (s, 1H), 6.12 (s, 1H), 4.55 (dd, J=4.4Hz, J=11.2Hz, 1H), 4.32 (dd, J=8.0Hz, J=11.2Hz, 1H), 2.64-2.70 (m, 1H), 1.88 (m, 1H), 1.60 (m, 1H), 1.03 (t, J =7.2Hz, 3H).
Referring to the synthetic method of embodiment 24, title compound is obtained by intermediate 34 and intermediate 65, yellow solid, is received Rate 19.8%, mp:147-149 DEG C；1H-NMR(400MHz,Acetone-d6) δ 12.86 (s, 1H), 4.76 (dd, J=4.4Hz, J =11.2Hz, 1H), 4.51 (dd, J=8.4Hz, J=11.2Hz, 1H), 3.90 (s, 2H), 3.77 (s, 3H), 3.13 (t, J= 7.2Hz, 2H), 2.71-2.77 (m, 1H), 2.10 (s, 3H), 1.92 (m, 1H), 1.61-1.76 (m, 3H), 1.06 (t, J= 7.2Hz, 3H), 0.97 (t, J=7.2Hz, 3H)；13C-NMR(100MHz,Acetone-d6)δ207.6,199.7,162.3, 162.0,161.2,161.0,159.2,158.1,112.0,110.0,108.9,106.9,102.5,102.4,71.6,62.1, 46.6,45.0,20.7,18.7,17.0,14.1,11.7,9.4；ESI-MS:calculated,478.92；found,479.46 [M+H]+.HR-MS(ESI):calculated,479.1467,C24H28ClO8,[M+H]+；found,479.1467,[M+H]+。
63 8- of embodiment (3- bytyry -2,6- dihydroxy -4- methoxyl group -5- aminomethyl phenyl) chloro- 3- methyl -5,7- of -6- Dihydroxy chroman-4-on
2,4,6- trihydroxy -3- chlorophenyl acetone (66)
Intermediate 66 is obtained referring to the synthetic method of intermediate 3, gray solid, yield 73%,1H-NMR(400MHz, DMSO-d6) δ 14.31 (s, 1H), 11.04 (s, 1H), 11.00 (s, 1H), 6.13 (s, 1H), 3.02 (q, J=7.2Hz, 2H), 1.04 (t, J=7.2Hz, 3H).
Chloro- 2, the 4- dimethoxy methoxybenzene acetone (67) of 6- hydroxyl -3-
Intermediate 67 is obtained referring to the synthetic method of intermediate 4, yellow solid, yield 43.2%,1H-NMR(400MHz, Acetone-d6)δ12.70(s,1H),6.59(s,1H),5.37(s,2H),5.23(s,2H),3.55(s,3H),3.49(s, 3H), 3.20 (q, J=7.2Hz, 2H), 1.13 (t, J=7.2Hz, 3H).
Chloro- 3- methyl -5, the 7- dimethoxy methoxyl group chroman-4-on (68) of 6-
Intermediate 68 is obtained referring to the synthetic method of intermediate 64, yellow oil, yield 79%,1H-NMR(400MHz, Acetone-d6) δ 6.61 (s, 1H), 5.37 (s, 2H), 5.14 (d, J=6.4Hz, 1H), 5.07 (d, J=6.4Hz, 1H), 4.53 (dd, J=4.8Hz, J=11.2Hz, 1H), 4.19 (t, J=10.8Hz, 1H), 3.59 (s, 3H), 3.49 (s, 3H), 2.72-2.78 (m, 1H), 1.12 (d, J=7.2Hz, 3H).
Chloro- 3- methyl -5, the 7- dihydroxy chroman-4-on (69) of 6-
Intermediate 69 is obtained referring to the synthetic method of intermediate 6, yellow solid, yield 71.4%,1H-NMR(400MHz, Acetone-d6) δ 12.84 (s, 1H), 9.89 (s, 1H), 6.12 (s, 1H), 4.53 (dd, J=5.2Hz, J=11.2Hz, 1H), 4.18 (t, J=11.2Hz, 1H), 2.92-3.01 (m, 1H), 1.19 (d, J=7.2Hz, 1H).
Referring to the synthetic method of embodiment 24, title compound is obtained by intermediate 34 and intermediate 69, yellow solid, is received Rate 22.4%, mp:169-171 DEG C,1H-NMR(400MHz,Acetone-d6) δ 13.11 (s, 1H), 4.55 (dd, J=4.8Hz, J =11.2Hz, 1H), 4.13 (t, J=10.8Hz, 1H), 3.84 (s, 2H), 3.70 (s, 3H), 3.04 (t, J=7.2Hz, 2H), 2.80-2.86 (m, 1H), 2.04 (s, 3H), 1.68 (m, 2H), 1.17 (d, J=6.8Hz, 3H), 0.95 (t, J=7.2Hz, 3H)；13C-NMR(100MHz,Acetone-d6)δ206.8,198.8,166.2,163.8,161.6,160.7,159.2, 158.6,111.8,111.0,108.6,108.0,102.7,101.0,72.9,61.9,45.0,39.9,18.9,17.5,14.2, 11.1,9.5；ESI-MS:calculated,464.89；found,463.25[M-H]-.HR-MS(ESI):calculated, 465.1311,C23H26ClO8,[M+H]+；found,465.1312,[M+H]+。
64 8- of embodiment (3- butyl -2,6- dihydroxy -4- methoxyl group -5- aminomethyl phenyl) chloro- 2- ethyl -5,7- two of -6- Hydroxy-2-methyl chroman-4-on
4- butyl -5- methoxyl group -6- aminomethyl phenyl -1,3- glycol (70)
In 25mL round-bottomed flask, raw material 6 (0.8mmol) is added and Zn powder (8mmol) is dissolved in 5mL methanol, is cooled to 0 DEG C, concentrated hydrochloric acid 1.2mL is added in careful dropwise, is added dropwise, and reaction solution is warmed to room temperature reaction 2.5h, reaction solution saturated salt solution Dilution, ethyl acetate extraction, organic phase merge, and saturated common salt washing, anhydrous sodium sulfate is dry, concentration, silica gel column layer chromatography (PE/EA=10:1) intermediate 70, yellow oil, yield 71.3%,1H-NMR(400MHz,Acetone-d6)δ7.77 (s, 1H), 7.74 (s, 1H), 6.24 (s, 1H), 3.65 (s, 3H), 2.54 (t, J=7.6Hz, 2H), 2.03 (s, 3H), 1.51 (m, 2H), 1.36 (m, 2H), 0.91 (t, J=7.2Hz, 3H).
Referring to the synthetic method of embodiment 24, title compound is obtained by intermediate 70 and intermediate 51a, yellow solid, Yield 11.7%, mp:127-129 DEG C；1H-NMR(400MHz,Acetone-d6)δ13.07(s,1H),3.73(s,2H),3.60 (s, 3H), 2.78 (d, J=17.2Hz, 1H), 2.65 (d, J=17.2Hz, 1H), 2.09 (s, 3H), 1.84-1.99 (m, 2H), 1.51 (s, 3H), 1.29-1.38 (m, 4H), 1.05 (t, J=7.2Hz, 3H), 0.91 (t, J=6.8Hz, 3H)；13C-NMR (100MHz,Acetone-d6)δ193.5,159.2,158.9,157.3,154.8,153.2,152.9,115.1,111.3, 109.9,109.6,108.9,102.3,83.4,60.8,45.6,33.5,32.6,24.7,23.7,19.5,14.4,9.7,8.5； ESI-MS:calculated,478.96；found,479.31[M-H]-.HR-MS(ESI):calculated,479.1831, C25H32ClO7,[M+H]+；found,479.1828,[M+H]+。
65 1- of embodiment (3- ((the chloro- 2- ethyl -5,7- dihydroxy -2- methyl chroman -8- base of 6-) methyl) -2,4- dihydroxy Base -6- methoxyl group -5- aminomethyl phenyl) butane
The chloro- 2- Ethyl-2-Methyl chroman -5,7- glycol (71) of 6-
Intermediate 71 is obtained referring to the synthetic method of intermediate 70, yellow solid, yield 60.4%,1H-NMR(400MHz, Acetone-d6)δ8.37(s,1H),7.74(s,1H),6.02(s,1H),2.53-2.66(m,2H),1.69-1.82(m,2H), 1.53-1.66 (m, 2H), 1.21 (s, 3H), 0.93 (t, J=7.2,3H).
Referring to the synthetic method of embodiment 24, title compound is obtained by intermediate 70 and intermediate 71, yellow solid, is received Rate 18.0%,1H-NMR(400MHz,Acetone-d6)δ15.50(s,1H),8.98(s,1H),8.73(s,1H),7.86(s, 1H), 3.84 (s, 2H), 3.78 (s, 3H), 3.15 (t, J=7.2Hz, 2H), 2.66 (t, J=6.8Hz, 2H), 2.08 (s, 3H), 1.78-1.96 (m, 4H), 1.68-1.76 (m, 2H), 1.43 (s, 3H), 1.04 (t, J=7.2Hz, 3H), 0.97 (t, J= 7.2Hz,3H)；13C-NMR(100MHz,Acetone-d6)δ208.0,162.2,161.3,160.4,151.2,151.0, 149.6,112.3,110.3,108.8,106.7,103.1,102.2,80.9,62.1,44.9,32.1,30.5,23.2,18.7, 17.7,17.1,14.1,9.3,8.4；ESI-MS:calculated,478.96；found,479.31[M+H]+；HR-MS (ESI):calculated,479.1831,C25H32ClO7,[M+H]+；found,479.1827,[M+H]+。
66 8- of embodiment (3- butyl -2,6- dihydroxy -4- methoxyl group -5- aminomethyl phenyl) chloro- 5,7- dihydroxy -3- of -6- Methyl chroman-4-on
Referring to the synthetic method of embodiment 24, title compound is obtained by intermediate 69 and intermediate 70, yellow solid, is received Rate 11.3%,1H-NMR(400MHz,Acetone-d6) δ 13.20 (s, 1H), 4.63 (dd, J=4.8Hz, J=10.8Hz, 1H), 4.22 (t, J=10.4Hz, 1H), 3.70 (s, 2H), 3.59 (s, 3H), 2.81-2.88 (m, 1H), 2.54 (t, J=7.6Hz, 2H), 2.02 (s, 3H), 1.44-1.52 (m, 2H), 1.32-1.39 (m, 2H), 1.20 (d, J=6.8Hz, 3H), 0.91 (t, J= 7.2Hz,2H)；13C-NMR(100MHz,Acetone-d6)δ196.1,171.4,159.7,157.2,156.6,153.4, 153.1,114.9,111.5,109.4,109.3,103.6,98.5,73.0,60.7,39.6,33.5,24.8,23.8,19.3, 14.4,11.4,9.7；ESI-MS:calculated,450.91；found,451.14[M+H]+.HR-MS(ESI): calculated,451.1518,C23H28ClO7,[M+H]+；found,451.1517,[M+H]+。
67 8- of embodiment (3- bytyry -2,6- dihydroxy -4- methoxyl group -5- aminomethyl phenyl) chloro- 2- ethyl -7- hydroxyl of -6- Base -5- methoxyl group -2- methyl chroman-4-on
The chloro- 7- of 6- (4- toluenesulfonic acid) -5- methoxyl group -2- Ethyl-2-Methyl chroman-4-on (72)
In 50mL round-bottomed flask, raw material 51a (0.4mmol), K are sequentially added2CO3(2.8mmol) and TsCl (0.4mmol), 25mL acetone solution, corresponding yellow solution are heated to reflux 5h, cooling, and K is added2CO3(1.2mmol) and Me2SO4(0.44mmol) is heated to reflux 20h, cooling, filters, and is concentrated under reduced pressure, and silica gel column chromatography (PE/EA=60:1) obtains intermediate Body 72, yellow oil, yield 74%,1H-NMR(400MHz,Acetone-d6) δ 7.85 (d, J=8.4Hz, 2H), 7.52 (d, J=8.4Hz, 2H), 6.75 (s, 1H), 3.77 (s, 3H), 2.82 (d, J=15.6Hz, 1H), 2.68 (d, J=16.0Hz, 1H), 2.48 (s, 3H), 1.69-1.87 (m, 2H), 1.38 (s, 3H), 0.97 (t, J=7.2Hz, 3H).
6- chloro-5-methoxyl -7- hydroxyl -2- Ethyl-2-Methyl chroman-4-on (73)
Under room temperature, three water of tetrabutyl ammonium fluoride is added into the tetrahydrofuran solution (5mL) of intermediate 72 (0.296mmol) It closes object (0.888mmol), stirs 3h, be concentrated under reduced pressure, residue is dissolved in 50mL ethyl acetate, is washed with 25mL, anhydrous slufuric acid Sodium is dry, and silica gel column chromatography obtains intermediate 73, light yellow solid, yield 62%,1H-NMR(400MHz,Acetone-d6)δ9.76 (br s, 1H), 6.38 (s, 1H), 3.81 (s, 3H), 2.69 (d, J=16.0Hz, 1H), 2.56 (d, J=16.0Hz, 1H), 1.68-1.83 (m, 2H), 1.35 (s, 3H), 0.95 (t, J=7.2Hz, 3H).
Referring to the synthetic method of embodiment 24, title compound is obtained by intermediate 34 and intermediate 73, yellow solid, is received Rate 11.6%, mp:201-203 DEG C,1H-NMR(400MHz,Acetone-d6)δ15.30(br,1H),9.04(br,2H),3.98 (s, 2H) 3.79 (s, 6H), 3.15 (t, J=7.2Hz, 2H), 2.79 (d, J=16.0Hz, 1H), 2.66 (d, J=16.0Hz, 1H),2.11(s,3H),1.80-1.95(m,2H),1.72(m,2H),1.47(s,3H),0.95-1.01(m,6H)；13C-NMR (100MHz,Acetone-d6)δ207.9,188.7,161.7,161.4,159.0,158.5,157.5,157.0,112.0, 111.9,111.3,110.3,109.4,109.0,84.2,62.2,61.5,48.2,45.0,32.3,23.3,18.7,17.7, 14.1,9.3,8.3；ESI-MS:calculated,506.97；found,507.37[M+H]+；HR-MS(ESI): calculated,507.1780,C26H32ClO8,[M+H]+；found,507.1780,[M+H]+。
The chloro- 2- ethyl -8- of 68 6- of embodiment ((3- ethyl -5,7- dihydroxy -8- methyl -4- chromanone -6- base) methyl) 5,7- dihydroxy -2- methyl chroman-4-on
3- ethyl -5,7- dimethoxy methoxyl group -8- methyl chroman-4-on (74)
Intermediate 74 is obtained referring to the synthetic method of intermediate 64, yellow oil, yield 82%,1H-NMR(400MHz, Acetone-d6) δ 6.55 (s, 1H), 5.28 (s, 2H), 5.15 (s, 2H), 4.53 (dd, J=4.4Hz, J=11.2Hz, 1H), 4.27 (dd, J=8.0Hz, J=11.2Hz, 1H), 3.46 (s, 3H), 3.45 (s, 3H), 2.39-2.45 (m, 1H), 2.04 (s, 3H), 1.82 (m, 1H), 1.49 (m, 1H), 0.99 (t, J=7.6Hz, 3H).
3- ethyl -5,7- dihydroxy -8- methyl chroman-4-on (75)
Intermediate 75 is obtained referring to the synthetic method of intermediate 6, white solid, yield 65%,1H-NMR(400MHz, Acetone-d6) δ 12.20 (s, 1H), 9.44 (s, 1H), 6.00 (s, 1H), 4.55 (dd, J=4.4Hz, J=11.2Hz, 1H), 4.30 (dd, J=8.0Hz, J=11.6Hz, 1H), 2.55-2.61 (m, 1H), 1.95 (s, 3H), 1.87 (m, 1H), 1.58 (m, 1H), 1.03 (t, J=7.6Hz, 3H).
6- ((dimethyl amido) methyl) -3- ethyl -5,7- dihydroxy -8- methyl chroman-4-on (76)
Intermediate 76 is obtained referring to the synthetic method of intermediate 34, yellow solid, yield 87%,1H-NMR(400MHz, Acetone-d6) δ 12.70 (br, 1H), 6.22 (br, 1H), 4.51 (dd, J=4.4Hz, J=11.2Hz, 1H), 4.27 (dd, J =8.0Hz, J=11.6Hz, 1H), 3.70 (s, 3H), 2.54-2.59 (m, 1H), 2.38 (s, 6H), 1.91 (s, 3H), 1.86 (m, 1H), 1.57 (m, 1H), 1.03 (t, J=7.6Hz, 3H).
Referring to the synthetic method of embodiment 24, title compound is obtained by intermediate 51a and intermediate 76, yellow solid, Yield 15.1%, mp:187-189 DEG C；1H-NMR(400MHz,Acetone-d6)δ13.53(s,1H),12.67(s,1H),8.91 (br, 1H), 4.56 (dd, J=4.4Hz, J=11.6Hz, 1H), 4.33 (dd, J=8.0Hz, J=11.2Hz, 1H), 3.88 (s, 2H), 2.94 (d, J=17.2Hz, 1H), 2.77 (d, J=17.2Hz, 1H), 2.61-2.68 (m, 1H), 1.99 (s, 3H), 1.88 (m, 3H), 1.61 (m, 1H), 1.46 (s, 3H), 1.04 (t, J=7.2Hz, 3H), 0.99 (t, J=7.6Hz, 3H)；13C-NMR (100MHz,Acetone-d6)δ200.9,197.8,162.6,160.3,159.7,159.2,158.4,156.6,107.6, 106.3,104.3,103.0,102.5,101.5,84.4,70.7,46.7,45.7,32.5,23.4,20.7,16.5,11.7, 8.3,7.9；ESI-MS:calculated,490.93；found,491.57[M+H]+；HR-MS(ESI):calculated, 491.1467,C25H28ClO8,[M+H]+；found,491.1467,[M+H]+。
The bromo- 2- ethyl -8- of 69 6- of embodiment ((3- ethyl -5,7- dihydroxy -8- methyl -4- chromanone -6- base) methyl) 5,7- dihydroxy -2- methyl chroman-4-on
Referring to the synthetic method of embodiment 24, title compound is obtained by intermediate 54a and intermediate 76, yellow solid, Yield 14.6%, mp:192-194 DEG C,1H-NMR(400MHz,Acetone-d6)δ13.66(s,1H),12.82(s,1H),8.90 (br, 2H), 4.57 (dd, J=4.4Hz, J=11.6Hz, 1H), 4.34 (dd, J=8.0Hz, J=11.2Hz, 1H), 3.89 (s, 2H), 2.96 (d, J=17.2Hz, 1H), 2.96 (d, J=17.2Hz, 1H), 2.80 (d, J=17.2Hz, 1H), 2.63-2.69 (m,1H),1.99(s,3H),1.84-1.97(m,3H),1.61(m,1H),1.49(s,3H),1.00-1.06(m,6H)；13C- NMR(100MHz,Acetone-d6)δ201.0,197.5,162.5,161.3,159.8,159.6,158.9,157.2,107.5, 106.2,104.4,103.1,102.5,91.3,84.6,70.7,46.6,45.7,32.5,23.4,20.7,16.7,11.7, 8.3,7.9；ESI-MS:calculated,535.38；found,535.29[M+H]+；HR-MS(ESI):calculated, 535.0962,C25H28BrO8,[M+H]+；found,535.0967,[M+H]+。
The chloro- 8- of 70 6- of embodiment ((3- ethyl -5,7- dihydroxy -8- methyl -4- chromanone -6- base) methyl) -5,7- two Hydroxy-3-methyl chroman-4-on
Referring to the synthetic method of embodiment 24, title compound is obtained by intermediate 69 and intermediate 76, yellow solid 13.4mg, yield 11.6%, mp:196-198 DEG C；1H-NMR(400MHz,Acetone-d6)δ13.04(s,1H),4.57(dd,J =4.8Hz, J=10.8Hz, 1H), 4.47 (dd, J=4.0Hz, J=11.2Hz, 1H), 4.24 (t, J=10.4Hz, 1H), 4.15 (t, J=10.4Hz, 1H), 3.81 (s, 2H), 2.83-2.91 (m, 1H), 2.51-2.57 (m, 1H), 1.93 (s, 3H), 1.82-1.89 (m, 1H), 1.53-1.60 (m, 1H), 1.18 (d, J=6.8Hz, 3H), 1.02 (t, J=7.2Hz, 3H)；13C- NMR(100MHz,Acetone-d6)δ199.8,198.8,165.7,160.2,159.20,159.15,158.9,108.3, 107.8,104.2,102.6,101.8,100.9,72.8,70.4,46.8,39.9,20.8,16.9,11.8,11.1,8.2； ESI-MS:calculated,462.88；found,463.18[M+H]+；HR-MS(ESI):calculated,463.1154, C23H24ClO8,[M+H]+；found,463.1151,[M+H]+。
The chloro- 8- of 71 6- of embodiment ((3- ethyl -5,7- dihydroxy -8- methyl -4- chromanone -6- base) methyl) -5,7- two Hydroxyl -2,2- dimethylchroman -4- ketone
Referring to the synthetic method of embodiment 24, title compound is obtained by intermediate 76 and intermediate 59a, yellow solid, Yield 8.6%, mp:214-216 DEG C；1H-NMR(400MHz,Acetone-d6)δ13.52(s,1H),12.72(s,1H),4.55 (dd, J=4.0Hz, J=11.2Hz, 1H), 4.32 (t, J=10.8Hz, 1H), 3.86 (s, 2H), 2.85 (s, 2H), 2.61- 2.64 (m, 1H), 1.98 (s, 3H), 1.83-1.90 (m, 1H), 1.56-1.63 (m, 1H), 1.51 (s, 6H), 1.03 (t, J= 7.2Hz,3H)；13C-NMR(100MHz,Acetone-d6)δ200.7,197.2,163.3,161.7,159.6,159.3, 158.5,156.7,108.1,106.6,104.3,102.5,102.3,81.6,70.6,47.7,46.7,26.4,20.7,16.7, 11.8,8.0；ESI-MS:calculated,476.90；found,477.26[M+H]+；HR-MS(ESI):calculated, 477.1311,C24H26ClO8,[M+H]+；found,477.1309,[M+H]+。
The chloro- 2- ethyl -8- of 72 6- of embodiment ((3- ethyl -7- hydroxy-5-methyl oxygroup -6- methyl -4- chromanone -8- base) Methyl) -5,7- dihydroxy -2- methyl chroman-4-on
4- methoxymethoxy -2- methoxyl group -6- hydroxy-3-methyl phenyl propyl ketone (77)
Intermediate 77 is obtained referring to the synthetic method of intermediate 4, yellow oil, yield 69.8%,1H-NMR (400MHz,Acetone-d6)δ13.13(s,1H),6.42(s,1H),5.30(s,2H),3.78(s,3H),3.46(s,3H), 3.10 (t, J=7.2Hz, 2H), 2.09 (s, 3H), 1.70 (t, J=7.2Hz, 2H), 0.96 (t, J=7.2Hz, 3H).
3- ethyl -5- methoxyl group -7- (methoxymethoxy) -6- methyl chroman-4-on (78)
Intermediate 78 is obtained referring to the synthetic method of intermediate 64, yellow oil, yield 92%,1H-NMR(400MHz, Acetone-d6) δ 6.44 (s, 1H), 5.29 (s, 2H), 4.48 (dd, J=4.4Hz, J=11.2Hz, 1H), 4.25 (dd, J= 8.0Hz, J=11.2Hz, 1H), 3.74 (s, 3H), 3.46 (s, 3H), 2.39-2.46 (m, 1H), 2.04 (s, 3H), 1.82 (m, 1H), 1.51 (m, 1H), 0.99 (t, J=7.6Hz, 3H).
3- ethyl -5- methoxyl group -7- hydroxyl -6- methyl chroman-4-on (79)
Intermediate 79 is obtained referring to the synthetic method of intermediate 6, white solid, yield 77.6%,1H-NMR(400MHz, Acetone-d6) δ 9.27 (s, 1H), 6.23 (s, 1H), 4.44 (dd, J=4.4Hz, J=11.2Hz, 1H), 4.20 (dd, J= 8.0Hz, J=11.2Hz, 1H), 3.73 (s, 3H), 2.35-2.41 (m, 1H), 2.02 (s, 3H), 1.81 (m, 1H), 1.50 (m, 1H), 0.98 (t, J=7.6Hz, 3H).
8- ((dimethyl amido) methyl) -3- ethyl -5- methoxyl group -7- hydroxyl -6- methyl chroman-4-on (80)
Intermediate 80 is obtained referring to the synthetic method of intermediate 34, yellow solid, yield 92.6%,1H-NMR(400MHz, Acetone-d6) δ 4.50 (dd, J=4.0, J=11.2,1H), 4.25 (dd, J=8.4, J=11.2,1H), 3.99 (s, 2H), 3.72(s,3H),2.61(s,6H),2.35-2.43(m,1H),2.02(s,3H),1.80(m,1H),1.51(m,1H),0.98 (t, J=7.2,3H).
Referring to the synthetic method of embodiment 24, title compound is obtained by intermediate 80 and intermediate 59a, yellow oily Object, yield 22.9%,1H-NMR(400MHz,Acetone-d6) δ 12.72 (br, 1H), 4.55 (dd, J=4.0Hz, J= 11.2Hz, 1H), 4.28 (m, 1H), 3.95 (m, 2H), 3.70 (s, 3H), 2.89 (d, J=17.2Hz, 1H), 2.89 (d, J= 17.2Hz, 1H), 2.71 (d, J=17.2Hz, 1H), 2.39-2.46 (m, 1H), 2.06 (s, 3H), 1.80 (m, 3H), 1.48 (m, 1H),1.39(s,1H),1.35(s,2H),0.91-0.99(m,6H)；13C NMR(101MHz,Acetone-d6)δ204.7, 196.4,190.2,159.1,159.0,158.5,157.9,156.7,155.8,111.7,108.7,107.9,106.5, 101.5,99.6,82.1,69.3,59.7,47.2,44.2,31.2,22.1,19.2,16.3,10.4,7.1,6.9,.ESI-MS: calculated,504.96；found,505.43[M+H]+；HR-MS(ESI):calculated,505.1624,C26H30ClO8, [M+H]+；found,505.1627,[M+H]+。
The chloro- 2- ethyl -5,7- dihydroxy -8- of 73 6- of embodiment ((6- hydroxyl -4- methoxyl group -5- methyl -3- propyl benzo [d] isoxazole -7- base) methyl) -2- methyl chroman-4-on
6- hydroxyl -4- methoxyl group -5- methyl -3- propyl benzo [d] isoxazole (81)
In 100mL round-bottomed flask, 6 (2.5mmol), hydroxylamine hydrochloride (5mmol) and sodium acetate (5mmol) is added, is dissolved in In 15mL ethyl alcohol and 5mL water, flow back 16h, is concentrated under reduced pressure, and suitable quantity of water is added, is extracted with ethyl acetate, and anhydrous sodium sulfate is dry, It is concentrated to give crude product, direct plunges into and reacts in next step.In 50mL round-bottomed flask, PPh is added3(3mmol) and DDQ (3mmol), It is dissolved in the dry DCM of 10mL, after 5min is stirred at room temperature, crude product oxime is added, 30min is stirred at room temperature, be concentrated under reduced pressure, silicon Plastic column chromatography (PE/EA=40:1) 81, white solid, yield 31%,1H-NMR(400MHz,Acetone-d6)δ8.41(s, 1H), 6.69 (s, 1H), 4.29 (s, 3H), 2.80 (t, J=7.2Hz, 2H), 2.11 (s, 3H), 1.84 (m, 2H), 1.02 (t, J =7.2Hz, 3H).
7- ((dimethyl amido) methyl) -6- hydroxyl -4- methoxyl group -5- methyl -3- propyl benzo [d] isoxazole (82)
Intermediate 82 is obtained referring to the synthetic method of intermediate 34, yellow oil, yield 85%,1H-NMR(400MHz, Acetone-d6) δ 4.26 (s, 3H), 3.83 (s, 2H), 2.81 (t, J=7.2Hz, 2H), 2.37 (s, 6H), 2.07 (s, 3H), 1.84 (m, 2H), 1.03 (t, J=7.2Hz, 3H).
Referring to the synthetic method of embodiment 24, title compound is obtained by intermediate 82 and intermediate 59a, yellow solid, Yield 13.3%, mp:166-168 DEG C；1H-NMR(400MHz,Acetone-d6)δ12.70(s,1H),4.23(s,3H),4.12 (s, 2H), 2.86 (d, J=17.2Hz, 1H), 2.81 (t, J=7.6Hz, 2H), 2.68 (d, J=17.2Hz, 1H), 2.15 (s, 3H), 1.84 (m, 2H), 1.73 (m, 2H), 1.28 (s, 3H), 1.00 (t, J=7.2Hz, 3H), 0.86 (t, J=7.2Hz, 3H) ；13C-NMR(100MHz,Acetone-d6)δ198.0,163.8,159.9,158.1,157.9,151.2,150.8,147.7, 125.9,111.4,107.9,104.3,103.1,100.6,82.9,60.6,45.7,32.7,30.9,23.5,20.9,19.0, 13.9,9.4,8.1；ESI-MS:calculated,489.95；found,490.39[M+H]+.HR-MS(ESI): calculated,490.1627,C25H29ClNO7,[M+H]+；found,490.1628,[M+H]+。
74 7,7 '-di-2-ethylhexylphosphine oxide of embodiment (4- methoxyl group -5- methyl -3- propyl benzo [d] isoxazole -6- alcohol)
Referring to the synthetic method of embodiment 24, title compound is obtained by intermediate 82, yellow solid, yield 16.2%, mp:192-194℃；1H-NMR(400MHz,Acetone-d6)δ8.40(s,2H),4.28(s,2H),4.23(s,6H),2.88 (t, J=7.2Hz, 4H), 2.15 (s, 6H), 1.90 (m, 4H), 1.05 (t, J=7.2Hz, 6H)13C-NMR(100MHz, Acetone-d6)δ164.2,150.7,147.9,126.0,111.6,104.3,60.6,30.9,21.0,19.7,14.0,9.5； ESI-MS:calculated,454.52；found,455.47[M+H]+；HR-MS(ESI):calculated,455.2177, C25H31N2O6,[M+H]+；found,455.2169,[M+H]+。
75 6- of embodiment (3- chloro- 2,4,6- trihydroxy -5- (2- methylbutyryl) phenyl) -3- ethyl -5,7- dihydroxy Base -8- methyl chroman-4-on
1- (the chloro- 2,4,6- trihydroxy phenyl of 3-) -2- methybutane -1- ketone (83)
In 50mL round-bottomed flask, raw material 50 (3.5mmol) and boron trifluoride ether (19.25mmol) is added, is dissolved in It in 15mL 1,2- dichloroethanes, after stirring 2min, is added 2- methylbutyryl chlorine (3.85mmol), flow back 3h, is concentrated under reduced pressure, residual Excess is extracted with EA and 3M HCl solution, stirs 10min, and organic phase is washed with saturated common salt, and anhydrous sodium sulfate is dry, dense Contracting, silica gel column chromatography (PE/EA=5:1) intermediate 83, light yellow oil, yield 82%,1H-NMR(300MHz,DMSO- d6)δ14.38(s,1H),11.12(s,1H),11.05(s,1H),6.13(s,1H),3.75(m,1H),1.69(m,1H),1.31 (m, 1H), 1.05 (d, J=6.6Hz, 3H), 0.83 (t, J=7.2Hz, 3H).
Referring to the synthetic method of embodiment 24, title compound is obtained by intermediate 83 and intermediate 76, yellow oil, Yield 19.7%,1H-NMR(400MHz,Acetone-d6) δ 14.05 (s, 1H), 10.20 (br, 1H), 4.58 (dd, J= 4.4Hz, J=11.2Hz, 1H), 4.34 (dd, J=8.0Hz, J=11.2Hz, 1H), 3.91 (m, 1H), 3.85 (s, 2H), 2.65-2.72 (m, 1H), 1.98 (s, 3H), 1.87 (m, 2H), 1.61 (m, 1H), 1.41 (m, 1H), 1.17 (d, J=6.8Hz, 3H), 1.04 (t, J=7.6Hz, 3H), 0.91 (t, J=7.6Hz, 3H)；13C-NMR(100MHz,Acetone-d6)δ211.7, 201.2,168.3,162.9,160.8,160.0,158.4,158.0,107.3,106.3,105.4,105.3,102.3, 102.1,70.7,46.7,46.5,27.6,20.6,16.9,16.3,12.2,11.7,7.9；ESI-MS:calculated, 478.92；found,479.46[M+H]+；HR-MS(ESI):calculated,C24H28ClO8,479.1467,[M+H]+； found,479.1466,[M+H]+。
76 6- of embodiment (the chloro- 2,4,6- trihydroxy -5- of 3- (2- ethylbutanoyl base) phenyl) -3- ethyl -5,7- dihydroxy Base -8- methyl chroman-4-on
1- (the chloro- 2,4,6- trihydroxy phenyl of 3-) -2- ethylbutane -1- ketone (84)
Intermediate 84 is obtained referring to the synthetic method of intermediate 83, yellow oil, yield 73%,1H-NMR(400MHz, Acetone-d6)δ13.67(s,1H),10.57(s,1H),9.57(s,1H),6.20(s,1H),3.87(m,1H),1.79(m, 2H), 1.51 (m, 2H), 0.88 (t, J=7.2Hz, 6H).
Referring to the synthetic method of embodiment 24, title compound is obtained by intermediate 84 and intermediate 76, yellow oil, Yield 10.2%,1H-NMR(400MHz,Acetone-d6) δ 14.06 (s, 1H), 10.14 (br, 1H), 4.58 (dd, J= 4.4Hz, J=11.2Hz, 1H), 4.34 (dd, J=8.0Hz, J=11.2Hz, 1H), 3.91 (m, 1H), 3.85 (s, 2H), 2.65-2.72(m,1H),1.98(s,3H),1.89(m,1H),1.81(m,2H),1.63(m,1H),1.53(m,2H),1.04 (t, J=7.2Hz, 3H), 0.89 (t, J=7.6Hz, 6H)；13C-NMR(100MHz,Acetone-d6)δ211.6,201.1, 162.8,162.6,160.0,158.3,158.1,157.6,107.2,106.2,106.1,105.4,102.3,102.0,70.7, 53.5,46.6,25.4,20.6,16.3,12.2,11.8,7.9；ESI-MS:calculated,492.95；found,493.55 [M+H]+.HR-MS(ESI):calculated,493.1624,C25H30ClO8,[M+H]+；found,493.1625,[M+H]+。
77 6,6 '-di-2-ethylhexylphosphine oxide of embodiment (3- ethyl -5,7- dihydroxy -8- methyl chroman-4-on)
Referring to the synthetic method of embodiment 24, title compound is obtained by intermediate 75, faint yellow solid, yield 21.5%, mp:208-210 DEG C；1H-NMR(400MHz,Acetone-d6) δ 13.96 (s, 2H), 9.04 (s, 2H), 4.58 (dd, J =4.4Hz, J=11.6Hz, 1H), 4.34 (dd, J=8.4Hz, J=11.2Hz, 1H), 3.78 (s, 2H), 2.65-2.71 (m, 1H), 1.96 (s, 6H), 1.88 (m, 2H), 1.61 (m, 2H), 1.04 (t, J=7.2Hz, 6H)；13C-NMR(100MHz, Acetone-d6)δ201.1,162.9,159.9,157.9,106.4,105.4,102.3,70.7,46.6,20.6,15.2, 11.7,7.9；ESI-MS:calculated,456.49；found,457.23[M+H]+.HR-MS(ESI):calculated, 457.1857,C25H29O8,[M+H]+；found,457.1855,[M+H]+。
78 8- of embodiment (3- chloro- 2,4,6- trihydroxy -5- (2- methylbutyryl) phenyl) -3- ethyl -7- hydroxyl -5- Methoxyl group -6- methyl chroman-4-on
Referring to the synthetic method of embodiment 24, title compound is obtained by intermediate 80 and intermediate 83, yellow oil, Yield 29.6%,1H-NMR(400MHz,Acetone-d6) δ 10.38 (br, 2H), 9.09 (br, 1H), 4.75 (dd, J= 4.0Hz, J=11.2Hz, 1H), 4.51 (m, 1H), 3.91 (s, 2H), 3.89 (m, 1H), 3.71 (s, 3H), 2.49-2.56 (m, 1H), 2.03 (s, 3H), 1.84 (m, 2H), 1.57 (m, 1H), 1.40 (m, 1H), 1.16 (d, J=6.8Hz, 3H), 1.02 (t, J =7.2Hz, 3H), 0.91 (t, J=7.6Hz, 3H)；13C NMR(101MHz,Acetone-d6)δ212.0,191.1,161.0, 160.5,159.89,158.4,158.3,156.9,114.5,109.3,109.2,106.9,105.3,101.8,71.50, 61.2,48.7,46.8,27.8,20.9,17.1,16.8,12.2,11.7,8.7.ESI-MS:calculated,492.95； found,493.25[M+H]+；HR-MS(ESI):calculated,493.1624,C25H30ClO8,[M+H]+；found, 493.1623,[M+H]+。
79 1- of embodiment (the chloro- 2,4,6- trihydroxy -5- of 3- (7- (6- hydroxyl -4- methoxyl group -5- methyl -3- propyl benzo [d] isoxazole) aminomethyl phenyl) -2- methyl butyl -1- ketone
Referring to the synthetic method of embodiment 24, title compound is obtained by intermediate 82 and intermediate 83, yellow solid, is received Rate 10.7%, mp:157-159 DEG C,1H-NMR(400MHz,Acetone-d6)δ13.98(br,1H),9.90(br,1H),8.80 (br, 2H), 4.23 (s, 3H), 4.14 (s, 2H), 3.89 (m, 1H), 2.81 (t, J=7.2Hz, 2H), 2.13 (s, 3H), 1.81- 1.87 (m, 3H), 1.40 (m, 1H), 1.15 (d, J=6.8Hz, 3H), 1.00 (t, J=7.2Hz, 3H), 0.90 (t, J= 7.2Hz,3H)；13C-NMR(100MHz,Acetone-d6)δ211.6,164.0,162.1,158.1,156.1,151.0, 150.7,147.8,126.0,111.4,107.9,105.6,104.1,101.3,60.6,46.8,30.8,27.6,20.9, 18.6,17.0,13.9,12.2,9.5；ESI-MS:calculated,477.93；found,478.29[M+H]+.HR-MS (ESI):calculated,478.1627,C24H29ClNO7,[M+H]+；found,478.1628,[M+H]+。
(((6- hydroxyl -4- methoxyl group -5- methyl -3- propyl benzo [d] is different by 7- by 2,4,6- trihydroxy -3- by 80 1- of embodiment Oxazole) methyl) -5- aminomethyl phenyl) ethyl ketone
Referring to the synthetic method of embodiment 24, title compound is obtained by intermediate 82 and intermediate 9, yellow solid, is received Rate 12.0%, mp:193-195 DEG C；1H-NMR(400MHz,Acetone-d6)δ10.64(s,1H),8.55(s,1H),4.23(s, 3H), 4.11 (s, 2H), 2.84 (s, J=7.2Hz, 2H), 2.65 (s, 3H), 2.15 (s, 3H), 2.08 (s, 3H), 1.87 (m, 2H), 1.02 (t, J=7.2Hz, 3H)；13C-NMR(100MHz,Acetone-d6)δ204.8,164.1,160.9,160.2, 160.0,150.6,150.5,147.8,125.9,111.5,106.36,106.35,104.6,103.6,60.6,33.1,30.8, 20.9,18.2,13.9,9.5,8.4；ESI-MS:calculated,415.44；found,416.37[M+H]+；HR-MS (ESI):calculated,416.1704,C22H26NO7,[M+H]+；found,416.1697,[M+H]+。
81 6- of embodiment (3- acetyl group -2,4,6- trihydroxy -5- aminomethyl phenyl) -3- ethyl -5,7- dihydroxy -8- first Base chroman-4-on
Referring to the synthetic method of embodiment 24, title compound is obtained by intermediate 76 and intermediate 9, yellow solid, is received Rate 18.3%, mp:207-209 DEG C；1H-NMR(400MHz,Acetone-d6) δ 13.99 (s, 1H), 4.56 (dd, J=4.4Hz, J =11.6Hz, 1H), 4.32 (dd, J=4.4Hz, J=11.6Hz, 1H), 3.77 (s, 2H), 2.67 (s, 3H), 2.60-2.65 (m, 1H), 2.07 (s, 3H), 1.97 (s, 3H), 1.81-1.94 (m, 1H), 1.55-1.66 (m, 1H), 1.04 (t, J=7.2Hz, 3H)；13C-NMR(100MHz,Acetone-d6)δ205.2,201.1,163.0,160.9,160.4,159.9,159.5, 157.9,107.0,106.0,105.8,105.2,104.4,102.3,70.7,46.5,33.0,20.6,16.1,11.8,8.3, 8.0；ESI-MS:calculated,416.42；found,417.32[M+H]+；HR-MS(ESI):calculated, 417.1544,C22H25O8,[M+H]+；found,417.1538,[M+H]+。
82 6- of embodiment (the chloro- 2,4,6- trihydroxy phenyl of 3- acetyl group -5-) -3- ethyl -5,7- dihydroxy -8- methyl Chroman-4-on
The chloro- 2,4,6- trihydroxy Phenyl ethyl ketone (85) of 3-
Intermediate 85 is obtained referring to the synthetic method of intermediate 83, yellow-brown solid, yield 60.2%,1H-NMR (400MHz,Acetone-d6)δ13.41(s,1H),10.58(s,1H),9.57(s,1H),6.19(s,1H),2.65(s,3H)。
Referring to the synthetic method of embodiment 24, title compound is obtained by intermediate 76 and intermediate 85, yellow solid, is received Rate 11.0%, mp:190-192 DEG C；1H-NMR(400MHz,Acetone-d6) δ 14.04 (s, 1H), 4.49 (dd, J=4.4Hz, J =11.6Hz, 1H), 4.32 (dd, J=4.4Hz, J=11.6Hz, 1H), 4.26 (dd, J=4.0Hz, J=10.8Hz, 1H), 3.74(s,2H),2.65(s,3H),2.54-2.60(m,1H),1.92(s,3H),1.83-1.90(m,1H),1.54-1.62(m, 1H), 1.03 (t, J=7.2Hz, 3H)；13C-NMR(100MHz,Acetone-d6)δ203.32,199.22,159.92, 159.47,158.73,157,70,157.09,106.81,106.36,104.50,100.67,100.51,99.96,69.58, 45.64,31.71,19.70,16.06,10.91,7.10；ESI-MS:calculated,436.84；found,435.22[M- H]-.HR-MS(ESI):calculated,437.0998,C21H22ClO8,[M+H]+；found,437.0994,[M+H]+。
83 6- of embodiment (the bromo- 2,4,6- trihydroxy phenyl of 3- acetyl group -5-) -3- ethyl -5,7- dihydroxy -8- methyl Chroman-4-on
The bromo- 2,4,6- trihydroxy Phenyl ethyl ketone (86) of 3-
Intermediate 86 is obtained referring to the synthetic method of intermediate 83, yellow solid, yield 29.7%,1H-NMR(400MHz, Acetone-d6)δ13.87(s,1H),10.31(s,1H),9.57(s,1H),6.23(s,1H),2.65(s,3H)。
Referring to the synthetic method of embodiment 24, title compound is obtained by intermediate 76 and intermediate 86, yellow solid, is received Rate 11.7%, mp:210-212 DEG C；1H-NMR(400MHz,DMSO-d6)δ13.18(s,1H),12.51(s,1H),4.47(dd,J =4.4Hz, J=11.2Hz, 1H), 4.23 (dd, J=4.0Hz, J=11.2Hz, 1H), 3.74 (s, 2H), 2.62 (s, 3H), 2.57-5.59 (m, 2H), 1.91 (s, 3H), 1.70-1.80 (m, 1H), 1.44-1.55 (m, 1H), 0.96 (t, J=7.2Hz, 3H)；13C-NMR(100MHz,DMSO-d6)δ202.8,199.1,163.6,160.7,160.4,158.3,157.9,157.8, 107.3,106.6,105.2,102.8,100.6,91.0,69.3,45.0,32.5,19.5,16.9,11.3,8.1；ESI-MS: calculated,481.29；found,481.15[M+H]+；HR-MS(ESI):calculated,481.0493,C21H22BrO8, [M+H]+；found,481.0491,[M+H]+。
84 6- of embodiment (the chloro- 2,4,6- trihydroxy phenyl of 3- bytyry -5-) -3- ethyl -5,7- dihydroxy -8- methyl Chroman-4-on
Referring to the synthetic method of embodiment 24, title compound is obtained by intermediate 76 and intermediate 66, yellow solid, is received Rate 11.0%, mp:137-139 DEG C；1H-NMR(400MHz,Acetone-d6)δ14.04(s,1H),10.29(br,2H),4.58 (dd, J=4.8Hz, J=11.2Hz, 1H), 4.34 (dd, J=11.2Hz, 1H), 3.84 (s, 2H), 3.15 (t, J=7.2Hz, 2H),2.65-2.71(m,1H),1.97(s,3H),1.83-1.92(m,1H),1.72(m,2H),1.57-1.64(m,1H), 1.04 (t, J=7.2Hz, 3H), 0.98 (t, J=7.2Hz, 3H)；13C-NMR(100MHz,Acetone-d6)δ207.9, 162.9,160.5,160.0,158.4,158.0,157.1,107.1,106.4,105.7,105.4,102.3,101.9,70.7, 46.56,46.53,20.6,18.6,16.2,14.1,11.7,7.9；ESI-MS:calculated,464.89；found, 465.16[M+H]+；HR-MS(ESI):calculated,465.1311,C23H26ClO8,[M+H]+；found,465.1309,[M +H]+。
85 6- of embodiment (the chloro- 2,4,6- trihydroxy phenyl of 3- propiono -5-) -3- ethyl -5,7- dihydroxy -8- methyl Chroman-4-on
The chloro- 2,4,6- trihydroxy benzene benzylacetone (87) of 3-
Intermediate 87 is obtained referring to the synthetic method of intermediate 83, gray solid, yield 73%,1H-NMR(400MHz, DMSO-d6) δ 14.31 (s, 1H), 11.04 (s, 1H), 11.00 (s, 1H), 6.13 (s, 1H), 3.02 (q, J=7.2Hz, 2H), 1.04 (t, J=7.2Hz, 3H).
Referring to the synthetic method of embodiment 24, title compound is obtained by intermediate 76 and intermediate 87, yellow solid, is received Rate 13.3%, mp:145-147 DEG C,1H-NMR(400MHz,Acetone-d6) δ 14.04 (s, 1H), 4.55 (dd, J=4.4Hz, J =11.6Hz, 1H), 4.31 (dd, J=11.2Hz, 1H), 3.80 (s, 2H), 3.18 (q, J=7.2Hz, 2H), 2.61-2.67 (m, 1H), 1.95 (s, 3H), 1.82-1.91 (m, 1H), 1.54-1.65 (m, 1H), 1.13 (t, J=7.6Hz, 3H), 1.03 (t, J=7.6Hz, 3H)；13C-NMR(100MHz,Acetone-d6)δ208.0,200.6,164.5,160.4,159.8,159.5, 158.03,157.95,107.5,106.9,105.34,105.32,101.9,101.6,70.6,46.5,37.8,20.6,16.7, 11.8,8.8,8.0；ESI-MS:calculated,450.87；found,449.24[M-H]-；HR-MS(ESI): calculated,451.1154,C22H24ClO8,[M+H]+；found,451.1150,[M+H]+。
86 1- of embodiment (3- bytyry -2,6- dihydroxy -4- methoxyl group -5- aminomethyl phenyl) chloro- tri- hydroxyl of 2,4,6- of -5- Base phenyl) -2- methyl butyl -1- ketone
Referring to the synthetic method of embodiment 24, title compound is obtained by intermediate 34 and intermediate 83, yellow oil, Yield 47%,1H-NMR(300MHz,Acetone-d6) δ 3.92 (m, 1H), 3.89 (s, 2H), 3.80 (s, 3H), 3.16 (t, J= 7.2Hz 2H), 2.10 (s, 3H), 1.85 (m, 1H), 1.72 (m, 2H), 1.41 (m, 1H), 1.17 (d, J=6.9Hz, 3H), 0.98 (t, J=7.2Hz, 3H), 0.91 (t, J=7.5Hz, 3H)；13C-NMR(150MHz,Acetone-d6)δ211.9, 208.0,161.7,161.5,160.4,159.6,158.3,156.6,112.7,109.6,109.0,107.0,105.2, 101.9,62.1,46.8,45.0,27.6,18.6,16.85,16.80,14.0,12.1,9.3；ESI-MS:calculated, 480.94；found,480.77[M+H]+；HR-MS(ESI):calculated,481.1629,C24H30ClO8,[M+H]+； found,481.1632,[M+H]+。
87 1- of embodiment (3- bytyry -2,6- dihydroxy -4- methoxyl group -5- aminomethyl phenyl) bromo- tri- hydroxyl of 2,4,6- of -5- Base phenyl) -2- methyl butyl -1- ketone
1- (the bromo- 2,4,6- trihydroxy phenyl of 3-) -2- methybutane -1- ketone (88)
Intermediate 88 is obtained referring to the synthetic method of intermediate 83, yellow oil, yield 46%,1H-NMR(300MHz, DMSO-d6)δ14.64(s,1H),11.21(s,1H),11.06(s,1H),6.18(s,1H),3.79(m,1H),1.71(m, 1H), 1.34 (m, 1H), 1.07 (d, J=6.3Hz, 3H), 0.85 (t, J=7.2Hz, 3H).
Referring to the synthetic method of embodiment 24, title compound is obtained by intermediate 34 and intermediate 88, yellow oil, Yield 43%,1H-NMR(400MHz,CDCl3)δ15.93(s,1H),15.74(s,1H),10.09(s,1H),9.30(s,1H), 3.87 (s, 2H), 3.77 (m, 1H), 3.72 (s, 3H), 3.07 (t, J=7.2Hz, 2H), 2.11 (s, 3H), 1.84 (m, 1H), 1.73 (m, 2H), 1.43 (m, 1H), 1.18 (d, J=6.8Hz, 3H), 0.99 (t, J=7.2Hz, 3H), 0.93 (t, J= 7.2Hz,3H)；13C-NMR(150MHz,CDCl3)δ210.8,207.0,161.6,160.4,159.4,112.3,109.0, 107.9,107.0,61.6,45.9,44.2,27.2,18.2,16.6,16.5,13.9,11.9,9.1；ESI-MS: calculated,525.40；found,525.16[M+H]+.HR-MS(ESI):calculated,525.1124, C24H30BrO8,[M+H]+；found,525.1136,[M+H]+。
88 3- of embodiment (3- bytyry -2,6- dihydroxy -4- methoxyl group -5- aminomethyl phenyl) -2,4,6- trihydroxy -5- (2- methylbutyryl) methyl benzoate
2,4,6- trihydroxy -3- (2- methylbutyryl) methyl benzoate (89)
Intermediate 89 is obtained referring to the synthetic method of intermediate 83, yellow oil, yield 61.1%,1H-NMR (400MHz,Acetone-d6)δ5.92(s,1H),4.10(s,3H),3.79(m,1H),1.83(m,1H),1.39(m,1H), 1.14 (d, J=6.4Hz, 3H), 0.90 (t, J=7.2Hz, 3H).
Referring to the synthetic method of embodiment 24, title compound is obtained by intermediate 24 and intermediate 89, yellow solid, is received Rate 50.0%, mp:137-139 DEG C；1H-NMR(300MHz,Acetone-d6)δ4.10(s,3H),3.89(s,2H),3.83(m, 1H), 3.74 (s, 3H), 3.09 (t, J=7.2Hz, 2H), 2.06 (s, 3H), 1.84 (m, 1H), 1.69 (m, 2H), 1.40 (m, 1H), 1.16 (d, J=6.9Hz, 3H), 0.96 (t, J=7.5Hz, 3H), 0.91 (t, J=7.5Hz, 3H)；13C-NMR (150MHz,Acetone-d6)δ212.1,207.3,160.8,111.1,109.8,109.0,62.0,53.8,47.0,45.1,27.4, 18.7,16.7,16.1,14.1,12.1,9.3；ESI-MS:calculated,504.52；found,504.71[M+H]+.HR- MS(ESI):calculated,505.2074,C26H33O10,[M+H]+；found,505.2081,[M+H]+。
89 5,5 '-di-2-ethylhexylphosphine oxide of embodiment (2,4,6- trihydroxy -3- (2- methylbutyryl) methyl benzoate)
Referring to the synthetic method of embodiment 24, title compound is obtained by intermediate 89, yellow oil, yield 27.3%,1H-NMR(300MHz,Acetone-d6)δ4.10(s,6H),3.86(s,2H),3.82(m,2H),1.80(m,2H), 1.38 (m, 2H), 1.13 (d, J=6.9Hz, 6H), 0.89 (t, J=7.2Hz, 6H)；ESI-MS:calculated,548.54； found,548.64[M+H]+；HR-MS(ESI):calculated,549.1972,C27H33O12,[M+H]+；found, 549.1976,[M+H]+。
90 1- of embodiment (3- (the bromo- 2,4,6- trihydroxy phenyl of 3,5- bis-) -2,4- dihydroxy -6- methoxyl group -5- methyl Phenyl) butyl -1- ketone
Referring to the synthetic method of embodiment 24, title compound is obtained by intermediate 34 and intermediate 53, yellow solid, is received Rate 12.0%, mp:178-180 DEG C,1H-NMR(400MHz,Acetone-d6)δ15.63(s,1H),9.21(s,2H),8.25(s, 1H), 3.95 (s, 2H), 3.79 (s, 3H), 3.16 (t, J=7.2Hz, 2H), 2.11 (s, 3H), 1.72 (m, 2H), 0.98 (t, J =7.2Hz, 3H)；13C-NMR(100MHz,Acetone-d6)δ208.1,161.3,160.4,159.7,152.2,151.4, 150.6,112.6,110.1,109.2,109.1,107.9,93.4,62.2,44.9,18.7,18.6,14.1,9.5；ESI-MS: calculated,520.17；found,519.20[M+H]+.HR-MS(ESI):calculated,518.9649, C19H21Br2O7,[M+H]+；found,518.9653,[M+H]+。
91 1- of embodiment (3- (the chloro- 2,4,6- trihydroxy phenyl of 3,5- bis-) -2,4- dihydroxy -6- methoxyl group -5- methyl Phenyl) butyl -1- ketone
Referring to the synthetic method of embodiment 24, title compound is obtained by intermediate 34 and intermediate 50 ', yellow solid, Yield 25.0%, mp:209-211 DEG C；1H-NMR(300MHz,Acetone-d6)δ3.92(s,2H),3.79(s,3H),3.15 (t, J=7.2Hz, 2H), 2.10 (s, 3H), 1.72 (m, 2H), 0.97 (t, J=7.5Hz, 3H)；13C-NMR(100MHz, Acetone-d6)δ208.0,161.5,159.8,150.5,149.8,112.6,109.9,109.1,107.6,102.5,99.6, 62.2,45.1,18.6,18.2,14.3,9.4；ESI-MS:calculated,431.26；found,431.31[M+H]+；HR- MS(ESI):calculated,431.0694,C19H21Cl2O7,[M+H]+；found,431.0679,[M+H]+。
92 3- of embodiment (3- bytyry -2,6- dihydroxy -4- methoxyl group -5- aminomethyl phenyl) chloro- tri- hydroxyl of 2,4,6- of -5- Yl benzoic acid methyl esters
The chloro- 2,4,6- trihydroxybenzoate (90) of 3-
In 50mL round-bottomed flask, it is added raw material (5mmol), is dissolved in 50mL chloroform, is cooled to 0 DEG C, is successively added dropwise 500 μ L ethyl alcohol, sulfonic acid chloride (5.125mmol) are concentrated under reduced pressure, silica gel column layer chromatographic purifying in 0 DEG C of stirring 3h, obtain 90, white is solid Body, yield 52%,1H-NMR(400MHz,Acetone-d6)δ10.79(s,1H),9.83(s,1H),9.69(s,1H),6.14 (s,1H),4.09(s,3H)。
Referring to the synthetic method of embodiment 24, title compound is obtained by intermediate 34 and intermediate 90, yellow solid, is received Rate 28.8%, mp:201-203 DEG C；1H-NMR(400MHz,Acetone-d6)δ15.69(br,1H),11.64(br s,1H), 10.37(s,1H),9.74(br s,1H),8.92(br s,1H),4.14(s,3H),3.88(s,2H),3.79(s,3H),3.15 (t, J=7.2Hz, 2H), 2.08 (s, 3H), 1.72 (m, 2H), 0.97 (t, J=7.2Hz, 3H)；13C-NMR(100MHz, Acetone-d6)δ208.1,171.1,162.0,161.5,160.5,159.3,157.3,156.5,112.6,109.6, 108.9,106.7,102.7,95.0,59.2,53.9,46.7,18.6,16.9,14.1,9.4；ESI-MS:calculated, 454.85；found,455.27[M+H]+；HR-MS(ESI):calculated,455.1103,C21H24ClO9,[M+H]+； found,455.1102,[M+H]+。
93 1- of embodiment (3- (3- chloro- 2,4,6- trihydroxy -5- (2- methylbutyryl) phenyl) -2,4- dihydroxy -6- Methoxyl group -5- aminomethyl phenyl) -2- methyl butyl -1- ketone
Referring to the synthetic method of embodiment 24, title compound is obtained by intermediate 18 and intermediate 83, yellow oil, Yield 13.2%,1H-NMR(400MHz,Acetone-d6)δ15.71(br,1H),10.14(br,1H),3.90(m,1H),3.89 (s, 2H), 3.80 (m, 1H), 3.78 (s, 3H), 2.10 (s, 3H), 1.83 (m, 2H), 1.43 (m, 2H), 1.17 (d, J= 6.4Hz, J=6.8Hz, 6H), 0.91 (t, J=7.6Hz 3H), 0.90 (t, J=7.2Hz, 3H)；13C-NMR(100MHz, Acetone-d6)δ212.5,212.0,162.2,161.3,161.0,160.6,158.7,156.8,113.0,110.0, 108.3,107.2,105.2,102.1,62.7,46.7,45.8,28.0,27.6,17.5,17.0,16.9,12.2,9.4；ESI- MS:calculated,494.96；found,495.31[M+H]+；HR-MS(ESI):calculated,495.1780, C25H32ClO8,[M+H]+；found,495.1783,[M+H]+。
94 1- of embodiment (3- bytyry -2,6- dihydroxy -4- methoxyl group -5- aminomethyl phenyl) chloro- tri- hydroxyl of 2,4,6- of -5- Benzaldehyde
The chloro- 2,4,6- tri hydroxybenzaldehyde (91) of 3-
Intermediate 91 is obtained referring to the synthetic method of intermediate 1, red brown solid, yield 82%,1H-NMR(400MHz, Acetone-d6)δ12.01(s,1H),10.36(s,1H),10.11(s,1H),9.94(s,1H),6.18(s,1H)。
Referring to the synthetic method of embodiment 24, title compound is obtained by intermediate 34 and intermediate 91, and yellow is solid, yield 9.4%, mp:194-196 DEG C；1H-NMR(400MHz,Acetone-d6)δ9.90(s,1H),3.76(s,2H),3.74(s,3H), 3.10 (t, J=7.2Hz, 2H), 2.05 (s, 3H), 1.71 (m, 2H), 0.97 (t, J=7.2Hz, 3H)；13C-NMR(100MHz, Acetone-d6)δ206.6,190.2,166.3,163.0,161.0,160.6,159.9,159.5,113.1,111.6, 108.5,107.3,104.5,101.1,61.8,44.5,18.9,18.2,14.2,9.5；ESI-MS:calculated, 424.83；found,425.25[M+H]+；HR-MS(ESI):calculated,425.0998,C20H22ClO8,[M+H]+； found,425.0993,[M+H]+。
95 1- of embodiment (3- bytyry -2,6- dihydroxy -4- methoxyl group -5- aminomethyl phenyl) chloro- tri- hydroxyl of 2,4,6- of -5- Base propiophenone
Referring to the synthetic method of embodiment 24, title compound is obtained by intermediate 34 and intermediate 87, yellow solid, is received Rate 14.4%, mp:160-162 DEG C；1H-NMR(400MHz,Acetone-d6)δ3.83(s,2H),3.75(s,3H),3.18(t,J =7.2Hz, 2H), 3.12 (t, J=7.2Hz, 2H), 2.06 (s, 3H), 1.71 (m, 2H), 1.13 (t, J=7.2Hz, 3H), 0.97 (t, J=7.6Hz, 3H)；13C-NMR(100MHz,Acetone-d6)δ207.5,207.0,165.0,161.3,161.0, 160.6,160.5,158.6,113.0,110.7,107.79,107.75,105.0,101.5,61.9,44.6,37.7,18.8, 17.7,14.2,9.5,9.0；ESI-MS:calculated,452.88；found,453.34[M+H]+；HR-MS(ESI): calculated,453.1311,C22H26ClO8,[M+H]+；found,453.1307,[M+H]+。
96 1- of embodiment (3- bytyry -2,6- dihydroxy -4- methoxyl group -5- aminomethyl phenyl) chloro- tri- hydroxyl of 2,4,6- of -5- Benzoylformaldoxime
Referring to the synthetic method of embodiment 24, title compound is obtained by intermediate 34 and intermediate 86, yellow solid, is received Rate 7.9%, mp:187-189 DEG C；1H-NMR(400MHz,Acetone-d6)δ11.15(br,3H),3.86(s,2H),3.77(s, 3H), 3.14 (t, J=7.2Hz, 2H), 2.69 (s, 3H), 2.08 (s, 3H), 1.72 (m, 2H), 0.97 (t, J=7.6Hz, 3H) ；13C-NMR(100MHz,Acetone-d6)δ207.6,204.6,163.5,161.4,161.3,161.0,160.4,159.3, 112.9,110.4,108.3,107.4,105.8,91.9,62.0,44.7,32.8,18.7,17.6,14.1,9.5；ESI-MS: calculated,483.31；found,483.28[M+H]+；HR-MS(ESI):calculated,483.0649,C21H24BrO8, [M+H]+；found,483.0644,[M+H]+。
97 3- of embodiment (3- bytyry -2,6- dihydroxy -4- methoxyl group -5- aminomethyl phenyl) chloro- tri- hydroxyl of 2,4,6- of -5- Benzaldehyde oxime
The chloro- 2,4,6- tri hydroxybenzaldehyde oxime (92) of 3-
In 25mL round-bottomed flask, hydroxylamine hydrochloride (8mmol) is added to Na2CO3Aqueous solution in (4mmol), to solid When dissolving and being released without gas, this aqueous solution is added in the ethyl alcohol for being dissolved in 1mL to raw material 91 (2mmol), is heated to 75 DEG C 3h is reacted, cooling, extraction, anhydrous sodium sulfate is dry, and concentration, column chromatography purifies (DCM/methanol=100:1), final 92, faint yellow solid, yield 37.1%,1H-NMR(400MHz,Acetone-d6)δ10.41(s,1H),10.39(s,1H), 9.45(s,1H),8.93(s,1H),8.53(s,1H),6.19(s,1H)。
Referring to the synthetic method of embodiment 24, title compound is obtained by intermediate 34 and intermediate 92, yellow solid, is received Rate 15.9%, mp:173-175 DEG C；1H-NMR(400MHz,Acetone-d6)δ15.67(s,1H),10.59(s,1H),9.71 (s, 1H), 8.58 (s, 1H), 3.88 (s, 2H), 3.79 (s, 3H), 3.16 (t, J=7.2Hz, 2H), 2.10 (s, 3H), 1.72 (m, 2H), 0.98 (t, J=7.2Hz, 3H)；13C-NMR(100MHz,Acetone-d6)δ208.1,162.0,161.5,160.4, 154.2,154.0,153.2,148.2,112.7,110.2,109.0,106.8,101.7,100.8,62.1,44.9,18.7, 17.3,14.1,9.4；ESI-MS:calculated,439.84；found,438.38[M-H]-；HR-MS(ESI): calculated,440.1107,C20H23ClNO8,[M+H]+；found,440.1100,[M+H]+。
98 3- of embodiment (3- bytyry -2,6- dihydroxy -4- methoxyl group -5- aminomethyl phenyl) chloro- tri- hydroxyl of 2,4,6- of -5- Benzaldehyde methoxy oxime
The chloro- 2,4,6- tri hydroxybenzaldehyde methoxy oxime (93) of 3-
Intermediate 93 is obtained referring to the synthetic method of intermediate 92, yellow solid, yield 73.3%,1H-NMR(400MHz, Acetone-d6)δ10.17(s,1H),9.42(s,1H),9.04(s,1H),8.50(s,1H),6.20(s,1H),3.93(s, 3H)。
Referring to the synthetic method of embodiment 24, title compound is obtained by intermediate 34 and intermediate 93, yellow solid, is received Rate 13.2%, mp:192-194 DEG C；1H-NMR(400MHz,Acetone-d6)δ15.69(s,1H),9.64(br,3H),8.55 (s, 1H), 3.98 (s, 3H), 3.89 (s, 2H), 3.79 (s, 3H), 3.16 (t, J=7.2Hz, 2H), 2.10 (s, 3H), 1.72 (m, 2H), 0.98 (t, J=7.2Hz, 3H)；13C-NMR(100MHz,Acetone-d6)δ208.1,161.9,161.5,160.4, 154.4,154.3,153.4,147.9,112.7,110.1,109.0,106.9,101.7,100.3,62.8,62.1,44.9, 18.6,17.3,14.1,9.4；ESI-MS:calculated,453.87；found,452.46[M-H]-；HR-MS(ESI): calculated,454.1263,C21H25ClNO8,[M+H]+；found,454.1255,[M+H]+。
The fluoro- 2- ethyl -8- of 99 6- of embodiment ((3- ethyl -5,7- dihydroxy -8- methyl -4- chromanone -6- base) methyl) 5,7- dihydroxy -2- methyl chroman-4-on
The fluoro- 2,4,6- trihydroxy benzene (94) of 1-
- 45 DEG C, to the CH of phloroglucin (7.94mmol)3F-TEDA-BF4 is added portionwise in CN (100ml) solution (9.52mmol) stirs 0.5h, is then stirred overnight at normal temperature, be concentrated under reduced pressure, and silica gel column chromatography (PE/EA=2:1) obtains Intermediate 94, yellow solid, yield 82.1%,1H-NMR(400MHz,DMSO-d6)δ9.36(s,2H),8.87(s,1H),5.81 (d, J=6.5Hz, 2H).
The fluoro- 2- ethyl -5,7- dihydroxy -2- methyl chroman-4-on (95) of 6- and the fluoro- 2- ethyl -5,7- dihydroxy -2- of 8- Methyl chroman-4-on (96)
Intermediate 95 is obtained referring to the synthetic method of intermediate 48, yellow solid, yield 45.1%,1H-NMR(400MHz, DMSO-d6) δ 11.76 (s, 1H), 5.93 (d, J=6.4Hz, 1H), 2.74-2.87 (m, 2H), 1.66-1.81 (m, 2H), 1.36 (s, 3H), 0.91 (t, J=7.4Hz, 3H)；And intermediate 96, yellow solid, yield 32.8%,1H-NMR(400MHz,DMSO) δ 11.99 (s, 1H), 11.31 (s, 1H), 5.97 (t, J=6.1Hz, 1H), 2.85-2.91 (m, 2H), 2.71-2.81 (m, 2H), 1.31 (s, 3H), 0.90 (t, J=7.6Hz, 3H).
Referring to the synthetic method of embodiment 24, title compound is obtained by intermediate 76 and intermediate 95, yellow solid, is received Rate 15.2%, mp:201-205 DEG C,1H-NMR(400MHz,Acetone-d6)δ13.69(br,2H),13.15(br,2H),4.57 (dd, J=11.4Hz, 4.5Hz, 1H), 4.33 (dd, J=11.3Hz, 8.0Hz, 2H), 3.84 (s, 2H), 2.91 (d, J= 17.3Hz, 1H), 2.80 (d, J=17.3Hz, 1H), 2.62-2.68 (m, 1H), 1.97 (s, 3H), 1.84-1.92 (m, 2H), 1.75-1.82 (m, 1H), 1.58-1.64 (m, 1H), 1.44 (s, 3H), 1.05 (t, J=7.5Hz, 3H), 0.99 (t, J= 7.4Hz,3H).13C-NMR(101MHz,Acetone-d6)δ200.1,197.1,161.9,158.9,157.6,154.0, 152.9,152.7,146.5,146.2,133.9,106.4,105.1,104.1,101.3,101.2,82.7,69.8,45.6, 45.3,31.6,22.6,19.7,14.3,10.8,7.2,7.0。ESI-MS:calcd for C25H27FO8[M+H]+:475.17； found,475.06。
100 2- ethyl -6- of embodiment ((3- ethyl -5,7- dihydroxy -8- methyl -4- chromanone -6- base) methyl) -8- Fluoro- 5,7- dihydroxy -2- methyl chroman-4-on
Referring to the synthetic method of embodiment 24, title compound is obtained by intermediate 76 and intermediate 96, yellow solid, is received Rate 17.3%, mp:139-141 DEG C；1H-NMR(400MHz,Acetone-d6)δ13.26(br,1H),12.09(s,1H),4.53 (dd, J=11.4Hz, 4.4Hz, 1H), 4.31 (dd, J=11.4Hz, 7.7Hz, 1H), 3.86 (s, 2H), 2.85 (d, J= 17.2Hz, 1H), 2.67 (d, J=17.1,1H), 2.52-2.64 (m, 1H), 1.98 (s, 3H), 1.79-1.87 (m, 2H), 1.52-1.69 (m, 2H), 1.39 (d, J=6.1Hz, 3H), 1.04 (t, J=7.5Hz, 3H), 0.96 (t, J=7.5Hz, 3H) .13C-NMR(101MHz,Acetone-d6)δ199.4,196.9,162.8,159.1,158.4,153.2,148.4,148.3, 133.7,107.3,106.1,106.0,103.0,101.3,100.94,100.92,82.3,69.6,45.8,45.0,31.6, 22.7,19.8,15.3,10.9,7.4,7.1。ESI-MS:calcd for C25H27FO8[M+H]+:475.17；found, 475.13。
101 6- cyano -2- ethyl -8- of embodiment ((3- ethyl -5,7- dihydroxy -8- methyl -4- chromanone -6- base) first Base) -5,7- dihydroxy -2- methyl chroman-4-on
1- cyano -2,4,6- trihydroxy benzene (97)
Intermediate 52 (0.9804mmol) and CuCN are dissolved in DMF (3ml), microwave reaction, 135 DEG C, 0.5h, are depressurized dense Contracting, silica gel column chromatography (PE/EA=1:1) obtain intermediate 97, yellow solid, yield 51%,1H-NMR(400MHz,DMSO-d6) δ9.86(s,2H),9.07(s,1H),5.71(s,2H).
6- cyano -2- ethyl -5,7- dihydroxy -2- methyl chroman-4-on (98) and 8- cyano -2- ethyl -5,7- dihydroxy Base -2- methyl chroman-4-on (99)
Intermediate 98 is obtained referring to the synthetic method of intermediate 48, yellow solid, yield 30%,1H-NMR(400MHz, Acetone) δ 12.46 (s, 1H), 10.78 (br, 1H), 6.07 (s, 1H), 2.96 (d, J=16.9Hz, 2H), 2.84 (d, J= 17.2Hz, 1H), 1.90-1.98 (m, 1H), 1.77-1.86 (m, 1H), 1.50 (s, 3H), 1.05 (t, J=7.4Hz, 3H)；And Intermediate 99, yellow solid, yield 17%,1H-NMR(400MHz,Acetone-d6)δ13.05(s,1H),11.15(br,1H), 6.09(s,1H),2.89-3.03(m,1H),2.71-2.81(m,1H),1.78-1.87(m,2H),1.44(s,3H),0.99(t, J=7.5Hz, 3H).
Referring to the synthetic method of embodiment 24, title compound is obtained by intermediate 76 and intermediate 98, yellow solid, is received Rate 11.3%, mp:211-213 DEG C；1H-NMR(400MHz,Acetone-d6)δ13.63(s,1H),12.92(br,1H),4.40- 4.49 (m, 1H), 4.18-4.28 (m, 1H), 3.63-3.84 (m, 2H), 2.70 (d, J=17.0Hz, 1H), 2.43-2.59 (m, 2H),1.92(s,3H),1.68-1.88(m,3H),1.50-1.63(m,1H),1.38(s,3H),0.96-1.05(m,6H).13C- NMR(101MHz,Acetone-d6)δ198.3,193.6,170.1,167.1,166.3,160.2,159.8,157.8,116.5, 109.1,107.7,102.8,100.6,97.6,83.8,80.4,69.4,45.9,44.4,32.3,23.1,19.9,16.0, 13.6,11.0,7.3。ESI-MS:calcd for C26H27NO8[M+H]+:481.17；found,482.18.
102 2- ethyl -6- of embodiment ((3- ethyl -5,7- dihydroxy -8- methyl -4- chromanone -6- base) methyl) -8- Cyano -5,7- dihydroxy -2- methyl chroman-4-on
Referring to the synthetic method of embodiment 24, title compound is obtained by intermediate 76 and intermediate 99, yellow solid, is received Rate 25.0%, mp:206-208 DEG C；1H-NMR(400MHz,Acetone-d6)δ13.50(br,2H),12.17(br,1H), 4.45-4.6 (m, 1H), 4.30-4.19 (m, 1H), 3.75 (s, 2H), 2.79 (d, J=16.3Hz, 1H), 2.69 (d, J= 16.9Hz,1H),1.93(s,3H),1.78-1.85(m,1H),1.65-1.77(m,1H),1.46-1.66(m,2H),1.41(s, 3H),0.90-1.10(m,6H).13C-NMR(101MHz,Acetone-d6)δ199.1,194.3,164.4,163.1,162.8, 158.7,158.4,152.1,114.4,107.6,106.7,103.7,101.1,99.6,82.3,72.9,69.5,45.7, 45.0,31.2,22.3,19.9,14.9,11.0,7.2,7.2。ESI-MS:calcd for C26H27NO8[M+H]+:482.17； found,482.40。
103 6- of embodiment (4- (the bromo- 5,7- dihydroxy -3- carbonyl -1- propylidene -1,3- dihydroisobenzofuran of 6-) first Base) -3- ethyl -5,7- dihydroxy -8- methyl chroman-4-on
2- bytyry -3,5- methyl dihydroxy benzoate (100)
Intermediate 100 is obtained referring to the synthetic method of intermediate 83, yellow solid, yield 88.3%,1H-NMR (400MHz,DMSO-d6)δ10.12(s,1H),9.98(s,1H),6.63(s,1H),6.52(s,1H),3.71(s,3H),2.71 (t, J=7.2Hz, 2H), 1.58 (m, 2H), 0.91 (t, J=7.4Hz, 3H).
The bromo- 3,5- methyl dihydroxy benzoate (101) of 2- bytyry -6-
Intermediate 101 is obtained referring to the synthetic method of intermediate 52, yellow solid, yield 42%,1H-NMR(400MHz, DMSO-d6) δ 10.52 (br, 1H), 10.25 (br, 1H), 6.41 (s, 1H), 3.86 (s, 3H), 2.85 (t, J=2.1Hz, 2H), 1.53 (dd, J=4.3,2.1Hz, 2H), 0.95 (t, J=2.2Hz, 3H).
Referring to the synthetic method of embodiment 24, title compound is obtained by intermediate 76 and intermediate 101, yellow solid, Yield 35.2%, mp:207-209 DEG C,1H-NMR(400MHz,CDCl3)δ14.39(s,1H),10.04(s,1H),9.35(s, 1H), 6.21 (s, 1H), 5.95 (t, J=7.9Hz, 1H), 4.46 (dd, J=11.4Hz, 3.9Hz, 1H), 4.22-4.32 (m, 3H), 2.45-2.58 (m, 3H), 1.91-2.03 (m, 4H), 1.58-1.66 (m, 1H), 1.15 (t, J=7.5Hz, 3H), 1.06 (t, J=7.4Hz, 3H)；13C-NMR(101MHz,Acetone-d6)δ199.8,171.3,162.7,159.0,157.2, 154.6,147.0,142.2,121.9,118.1,116.4,116.0,108.6,105.6,103.8,101.4,45.9,20.1, 19.7,17.3,14.0,11.6,7.7。ESI-MS:calcd for C24H23BrO8[M+H]+:519.06；found,519.44.
The bromo- 8- of 104 6- of embodiment (6- (3- ethyl -5,7- dihydroxy -8- methyl -4- chromanone) methyl) -5,7- dihydroxy - 4 (1H) -one of base -2- methyl -2,3- dihydroquinoline
3- ((3,5- Dimethoxyphenyl) amido ethyl butyrate (102)
Under room temperature, 3,5- dimethoxyanilines (10mmol), the two of ethyl acetoacetate (60mmol) and acetic acid (30 μ L) Chloroethanes (30mL) solution stirs 20hs, is added sodium cyanoborohydride (40mmol), stirs 20hs, stops reaction, unsaturated carbonate It is 7 that sodium solution, which is added to PH, and extraction, anhydrous sodium sulfate is dry, is concentrated under reduced pressure, during silica gel column chromatography (PE/EA=10:1) obtains Mesosome 102, yellow solid, yield 85.2%,1H-NMR(400MHz,CDCl3)δ5.89(s,1H),5.83(s,2H),4.14(q, J=7.1Hz, 2H), 3.85-3.92 (m, 1H), 3.75 (s, 6H), 2.63 (dd, J=15.0Hz, 5.1Hz, 1H), 2.43 (dd, J =15.0Hz, 6.8Hz, 1H), 1.221.29 (m, 6H).
3- ((3,5- Dimethoxyphenyl) amido butyric acid (103)
Under room temperature, to the THF/H of intermediate 102 (12mmol)2Lithium hydroxide is added in O (v/v=20mL/20mL) (96mmol) stirs 20hs, stops reaction, it is 7 that 2N HCl solution, which is added to PH, and extraction, anhydrous sodium sulfate is dry, is concentrated under reduced pressure Obtain intermediate 103, colorless oil, yield 96.2%,1H-NMR(400MHz,DMSO-d6)δ6.2-6.4(m,3H),3.80- 3.83 (m, 1H), 3.73 (s, 6H), 2.67-2.70 (m, 1H), 2.40-2.51 (m, 1H), 1.23 (d, J=5.9Hz, 3H).
- 4 (1H) -one (104) of 5,7- dihydroxy -2- methyl -2,3- dihydroquinoline
Under room temperature, hydrobromic acid acetum (8ml) is added to intermediate 103 (12mmol), is heated to reflux 2hs, it is cooling, subtract Pressure concentration, silica gel column chromatography (PE/EA=2:1) obtain intermediate 104, yellow solid, yield 42.0%,1H-NMR(400MHz, DMSO-d6)δ12.65(s,1H),10.17(s,1H),6.79(s,1H),5.62(s,1H),5.43(s,1H),3.56-3.62 (dm, 1H), 2.35-2.47 (m, 2H), 1.20 (d, J=6.3Hz, 3H).
Bromo- 5,7- dihydroxy -2- methyl -2,3- dihydroquinoline -4 (1H) -one (105) of 6- and the bromo- 5,7- dihydroxy -2- of 8- Methyl -2,3- dihydroquinoline -4 (1H) -one (106)
Intermediate 105 is obtained referring to the synthetic method of intermediate 52, yellow solid, yield 31%,1H-NMR(400MHz, DMSO-d6)δ13.45(s,1H),11.03(s,1H),6.99(s,1H),5.87(s,1H),3.32-3.63(m,1H),2.37- 2.48 (m, 2H), 1.20 (d, J=6.2Hz, 3H)；And intermediate 106, yellow solid, yield 30%,1H-NMR(400MHz, DMSO)δ12.78(s,1H),11.15(s,1H),6.06(s,1H),5.75(s,1H),3.70-3.76(m,1H),2.61-2.67 (m, 1H), 2.40-2.50 (m, 1H), 1.25 (d, J=6.4Hz, 3H).
Referring to the synthetic method of embodiment 24, title compound is obtained by intermediate 76 and intermediate 105, yellow solid, Yield 27.8%, mp:193-195 DEG C,1H-NMR(400MHz,DMSO-d6)δ13.78(s,1H),13.59(br,1H),6.26 (s, 1H), 4.40 (dd, J=7.3Hz, 3.8Hz, 1H), 4.16 (dd, J=7.5Hz, 3.5Hz, 1H), 3.44 (s, 3H), 2.28- 2.42 (m, 2H), 1.73-1.90 (m, 4H), 1.44-1.54 (m, 1H), 1.24 (d, J=6.1Hz, 3H), 0.96 (t, J= 7.3Hz,3H)；13C-NMR(101MHz,DMSO-d6)δ197.1,194.1,170.1,169.2,159.3,157.6,157.5, 129.5,107.6,104.0,103.1,98.7,98.3,89.5,68.9,48.5,44.7,42.9,21.9,19.7,18.5, 11.3,8.1。ESI-MS:calcd for C23H24BrNO7[M+H]+:506.07；found,506.46.
The bromo- 6- of 105 8- of embodiment (6- (3- ethyl -5,7- dihydroxy -8- methyl -4- chromanone) methyl) -5,7- dihydroxy - 4 (1H) -one of base -2- methyl -2,3- dihydroquinoline
Referring to the synthetic method of embodiment 24, title compound is obtained by intermediate 76 and intermediate 106, yellow solid, Yield 35.7%, mp:210-212 DEG C,1H-NMR(400MHz,Acetone-d6)δ14.70(s,1H),13.99(s,1H),9.19 (br, 2H), 5.76 (s, 1H), 4.59 (dd, J=11.4Hz, 4.5Hz, 1H), 4.35 (dd, J=11.4Hz, 4.5Hz, 1H), 3.88-3.96(m,1H),3.79(s,2H),2.66-2.77(m,2H),2.54-2.61(m,1H),1.98(s,3H),1.84- 1.96 (m, 1H), 1.58-1.67 (m, 1H), 1.40 (d, J=6.4Hz, 3H), 1.06 (t, J=7.5Hz, 3H)；13C-NMR (101MHz,Acetone-d6)δ205.2,200.2,198.2,161.9,159.9,159.1,158.9,156.9,149.1, 105.7,104.2,102.6,101.5,100.4,86.7,69.81,47.6,45.4,42.6,19.75,19.71,14.5, 10.8,6.8。ESI-MS:calcd for C23H24BrNO7[M+H]+:506.07；found,506.63.
106 6,6 '-di-2-ethylhexylphosphine oxide of embodiment (bromo- 5,7- dihydroxy -2- methyl -2,3- dihydroquinoline -4 (1H) -one of 8-)
Referring to the synthetic method of embodiment 1, title compound is obtained by intermediate 106, yellow solid, yield 34.9%, Mp:202-204 DEG C,1H-NMR(400MHz,DMSO-d6)δ13.45(s,2H),9.81(br,2H),5.92(s,2H),3.70(s, 4H),2.59-2.80(m,2H),2.25-2.45(m,2H),1.24(s,6H)；13C-NMR(101MHz,DMSO-d6)δ197.1, 160.3,147.9,103.3,100.1,86.4,47.1,42.6,20.0,16.0。
The bromo- 3- ethyl -5,7,9- trihydroxy -13- methyl -6,11- dihydro -2H- benzene of 107 8- acetyl group -10- of embodiment And tall and erect [3,2] chroman -4 (3H) -one of [5,6] oxa-
4- methyl -2,6- resacetophenone (107)
Intermediate 107 is obtained referring to the synthetic method of intermediate 3, yellow solid, yield 84.3%,1H-NMR(400MHz, CDCl3)δ9.51(s,2H),6.22(s,2H),2.72(s,3H),2.24(s,3H)。
4- methyl -2,6- diacetoxy acetophenone (108)
Intermediate 108 is obtained referring to the synthetic method of embodiment 22, white solid, yield 96.0%,1H-NMR (400MHz,CDCl3)δ6.85(s,2H),2.44(s,3H),2.37(s,3H),2.27(s,6H)。
4- bromomethyl -2,6- diacetoxy acetophenone (109)
At room temperature, under nitrogen protection, NBS is added into carbon tetrachloride (30ml) solution of intermediate 108 (11.2mmol) (11.76mmol) and AIBN (25mg), is heated to reflux 3hs, is concentrated under reduced pressure, and silica gel column chromatography (PE/EA=5:1) obtains intermediate 109, yellow solid, yield 51.0%,1H-NMR(400MHz,CDCl3)δ7.12(s,2H),4.44(s,2H),2.48(s,3H), 2.30(s,6H)。
4- bromomethyl -2,6- resacetophenone (110)
At room temperature, the concentrated sulfuric acid (2 drop) is added into methanol (1ml) solution of intermediate 109 (20mg), heats 50 degree of 1h, It being concentrated under reduced pressure, silica gel column chromatography (PE/EA=2:1) obtains intermediate 110, yellow solid, yield 88.1%,1H-NMR (400MHz,DMSO-d6)δ11.87(s,2H),6.45(s,2H),4.53(s,2H),2.63(s,3H)。
Bromo- 2, the 6- resacetophenone (111) of 4- bromomethyl -3-
At room temperature, NBS (2.15mmol) is added into methylene chloride (25ml) solution of intermediate 110 (2.1mmol), stirs 1h to be mixed, is concentrated under reduced pressure, silica gel column chromatography (PE/EA=5:1) obtains intermediate 111, yellow solid, yield 80.0%,1H-NMR (400MHz,Acetone-d6)δ6.77(s,1H),4.62(s,2H),2.75(s,3H)。
6- (3- acetyl group -5- bromo- 6- (bromomethyl) -2,4- dihydroxy phenyl) -3- ethyl -5,7- dihydroxy -8- methyl Chroman-4-on (112)
Referring to the synthetic method of embodiment 1, title compound is obtained by intermediate 75 and intermediate 111, yellow solid, is received Rate 89.1%,1H-NMR(400MHz,Acetone-d6) δ 13.28 (s, 1H), 5.04 (s, 2H), 4.54 (dd, J=11.3Hz, 4.3Hz, 1H), 4.31 (dd, J=11.2Hz, 7.9Hz, 1H), 4.04 (s, 2H), 2.80 (s, 3H), 2.58-2.63 (m, 1H), 1.98 (s, 3H), 1.82-1.92 (m, 1H), 1.54-1.64 (m, 1H), 1.04 (t, J=7.5Hz, 3H).
Under room temperature, cesium carbonate (0.45mmol) is added into acetone (20ml) solution of intermediate 112 (0.036mmol), 5hs is stirred, is filtered, is concentrated under reduced pressure, TLC plate layer chromatography (PE/EA=5:1) obtains title compound, yellow solid, yield 26.8%, mp:207-209 DEG C,1H-NMR(400MHz,DMSO-d6)δ12.79(s,1H),11.65(br,2H),5.59(s, 2H), 4.49 (dd, J=11.3Hz, 4.1Hz, 1H), 4.32-4.15 (m, 3H), 2.58-2.72 (m, 4H), 1.83 (s, 3H), 1.70-1.77 (m, 1H), 1.45-1.55 (m, 1H), 0.95 (t, J=7.4Hz, 3H)13C-NMR(101MHz,DMSO-d6)δ 205.6,200.3,163.1,158.8,157.9,156.9,155.0,142.0,121.3,114.2,106.2,105.3, 103.2,102.6,70.4,69.8,45.8,33.5,19.9,18.2,11.67,8.2。ESI-MS:calcd for C22H21BrO7 [M+H]+:477.05；found,477.26.
The chloro- 3- ethyl -5,7,9- trihydroxy -13- methyl -6,11- dihydro -2H- benzene of 108 8- acetyl group -10- of embodiment And tall and erect [3,2] chroman -4 (3H) -one of [5,6] oxa-
The chloro- 2,6- dihydroxy -4- methyl acetophenone (113) of 3-
Under room temperature, NCS (0.03mmol) and chlorine are added into acetonitrile (100ml) solution of intermediate 107 (0.03mmol) Change aluminium (200mg), stir 2hs, filter, is concentrated under reduced pressure, C18Silica gel column chromatography (PE/EA=2:1) obtains intermediate 113, yellow Solid, yield 87%,1H-NMR(400MHz,DMSO-d6)δ6.31(s,1H),2.62(s,3H),2.26(s,3H)。
Chloro- 4- methyl -2, the 6- diacetoxy acetophenone (114) of 3-
Intermediate 114 is obtained referring to the synthetic method of intermediate 108, yellow solid, yield 96.1%,1H-NMR (400MHz,DMSO-d6)δ7.28(s,1H),2.40(s,6H),2.33(s,3H),2.27(s,3H)。
Chloro- 4- bromomethyl -2, the 6- diacetoxy acetophenone (115) of 3-
Intermediate 115 is obtained referring to the synthetic method of intermediate 109, yellow solid, yield 93.1%,1H-NMR (400MHz,DMSO-d6)δ7.57(s,1H),4.76(s,2H),2.42(s,3H),2.35(s,3H),2.29(s,3H)。
Chloro- 4- bromomethyl -2, the 6- resacetophenone (116) of 3-
Intermediate 116 is obtained referring to the synthetic method of intermediate 110, yellow solid, yield 92.1%,1H-NMR (400MHz,DMSO-d6)δ13.38(s,1H),11.33(s,1H),6.66(s,1H),4.63(s,2H),2.67(s,3H)。
Intermediate 117, yellow solid are obtained referring to the synthetic method of intermediate 112, yield 67.1% direct plunges into next Step.
Title compound, yellow solid, yield 39.1%, mp:221-223 are obtained referring to the synthetic method of embodiment 107 DEG C,1H-NMR(400MHz,DMSO-d6)δ12.76(s,1H),12.51(br,1H),10.83(br,1H),5.54(s,2H), 4.49 (dd, J=11.3Hz, 4.3Hz, 1H), 4.25 (dd, J=11.1Hz, 8.1Hz, 1H), 4.19 (s, 2H), 2.60-2.71 (m, 4H), 1.87 (s, 3H), 1.70-1.79 (m, 1H), 1.44-1.55 (m, 1H), 0.95 (t, J=7.5Hz, 3H)13C-NMR (101MHz,DMSO-d6)δ205.6,200.3,163.2,158.7,157.9,156.8,153.9,140.6,120.5,113.3, 111.1,106.5,105.4,102.6,69.8,67.6,45.8,33.7,19.9,17.9,11.7,8.1。ESI-MS:calcd for C22H21ClO7[M+H]+:433.10；found,433.76.
109 1- of embodiment (the bromo- 1,8,10- trihydroxy -3- methoxyl group -4- methyl -6,11- dihydro two of 9- acetyl group -7- Benzo [b, e] oxa- Zhuo -2- base) chroman -1- ketone
Referring to the synthetic method of embodiment 107, title compound is obtained by intermediate 6 and intermediate 111, yellow solid, Yield 38.3%, mp:202-204 DEG C,1H-NMR(400MHz,DMSO-d6)δ13.52(s,1H),12.05(br,1H),10.95 (br, 1H), 5.59 (s, 2H), 4.28 (s, 2H), 3.64 (s, 3H), 3.02 (t, J=7.1Hz, 2H), 2.67 (s, 3H), 1.96 (s, 3H), 1.57-1.65 (m, 2H), 0.90 (t, J=7.3Hz, 3H)13C-NMR(101MHz,DMSO-d6)δ206.1, 205.1,161.0,159.2,158.4,156.4,154.4,141.6,120.6,113.6,112.1,109.7,109.6, 102.5,69.8,61.5,44.1,32.9,18.2,17.5,13.6,8.7。ESI-MS:calcd for C22H23BrO7[M+H]+: 479.06；found,479.24.
The 110 bromo- 5,10,12- trihydroxy -2,2,6- trimethyl -8,13- dihydroxy -2H- of 11- acetyl group -9- of embodiment Benzo [5,6] oxa- Zhuo [2,3] chroman -4 (3H) -one
Referring to the synthetic method of embodiment 107, title compound is obtained by intermediate 48a and intermediate 111, and yellow is solid Body, yield 36.1%, mp:196-198 DEG C,1H-NMR(400MHz,DMSO-d6)δ12.25(s,1H),12.15(br,1H), 10.91(br,1H),5.59(s,2H),4.23(s,2H),2.82(s,2H),2.68(s,3H),1.87(s,3H),1.42(s, 6H)；13C-NMR(101MHz,DMSO-d6)δ205.2,197.5,162.7,158.1,156.5,155.3,154.4,141.5, 120.8,113.6,105.6,102.5,102.1,79.0,69.8,46.6,33.0,26.1,18.2,7.2。ESI-MS:calcd for C22H21BrO7[M+H]+:477.05；found,477.55.
The 111 chloro- 5,10,12- trihydroxy -2,2,6- trimethyl -8,13- dihydroxy -2H- of 11- acetyl group -9- of embodiment Benzo [5,6] oxa- Zhuo [2,3] chroman -4 (3H) -one
Referring to the synthetic method of embodiment 107, title compound is obtained by intermediate 48a and intermediate 116, and yellow is solid Body, yield 32.8%, mp:211-213 DEG C,1H-NMR(400MHz,DMSO-d6)δ12.60(s,1H),12.25(s,1H), 10.80(s,1H),5.54(s,2H),4.19(s,2H),2.83(s,2H),2.69(s,3H),1.87(s,3H),1.42(s, 6H).13C-NMR(101MHz,DMSO-d6)δ205.1,197.5,162.8,158.0,156.4,155.2,153.4,140.0, 119.9,112.6,110.4,105.9,105.8,102.1,78.9,67.1,46.6,33.2,26.1,17.8,7.1。ESI-MS: calcd for C22H21ClO7[M+H]+:433.10；found,433.76.
The bromo- 5,7,9- trihydroxy -2,2,13- trimethyl -6,11- dihydroxy -2H- benzene of 112 8- acetyl group -10- of embodiment And tall and erect [2,3] chroman -4 (3H) -one of [5,6] oxa-
Referring to the synthetic method of embodiment 107, title compound is obtained by intermediate 48a ' and intermediate 111, and yellow is solid Body, yield 32.8%, mp:211-213 DEG C,1H-NMR(400MHz,DMSO-d6)δ12.69(s,1H),12.03(br,1H), 10.97(br,1H),5.60(s,2H),4.23(s,2H),3.18(s,3H),2.80(s,2H),2.68(s,3H),1.86(s, 3H),1.37(s,6H).13C-NMR(101MHz,DMSO-d6)δ205.1,197.3,162.9,157.8,156.2,155.7, 154.4,141.5,120.9,113.7,105.4,104.9,102.7,101.8,78.6,69.7,48.5,46.6,32.9, 26.1,17.6,7.8。ESI-MS:calcd for C22H21BrO7[M+H]+:477.05；found,477.44.
113 N- of embodiment (2- (4- ((3- bytyry -3,5- dihydroxy -6- methyl -4- (2,4,6- trihydroxy -3- first Base -5- (2- methylbutyryl) phenyl) phenoxy group) methyl) -1H-1,2,3- triazol-1-yl) ethyl) -5- ((3S, 4S, 6R) - 2- hexahydro -1H- [3,4-d] imidazol-4 yl) pentanamide
Under room temperature, 2- bromoethylamine (1mmol) is dissolved in 2mL water, is added sodium azide (3mmol), 80 DEG C of reactions, 18h Stop heating afterwards, after reaction solution is cooled to room temperature, be added with stirring 10mg potassium hydroxide at 0 DEG C, after 5min, with ether extraction three Secondary, colorless oil is concentrated under reduced pressure to obtain in combined ether layer, yield: 60~80%.
Biotin (1mmol), HOSu (1.07mmol) are dissolved in 12mL DMF, and lower addition EDC.HCl is stirred at room temperature (1.17mmol) continues that reaction is stirred at room temperature, and decompression steams DMF afterwards for 24 hours, residue obtained to be washed 3 times with MeOH, biologically final Plain Acibenzolar, yield: 89%.
Biotin Acibenzolar (1mmol) and 2- azidoethylamine (1.5mmol) are dissolved in 3mLDMF, after TEA (6mmol) is added Reaction is stirred at room temperature, stirs 16h, decompression steams DMF, the white solid 118 through column chromatography (DCM/MeOH=20:1) after purification, Yield: 84%,1H-NMR(300MHz,DMSO-d6) δ 8.02 (t, J=5.8Hz, 1H), 6.40 (s, 1H), 6.34 (s, 1H), 4.23-4.34(m,1H),4.03-4.15(m,1H),3.27-3.37(m,1H),3.14-3.24(m,2H),3.05-3.14(m, 2H), 2.81 (dd, J=12.4Hz, 5.0Hz, 1H), 2.56 (d, J=12.3Hz, 1H), 2.06 (t, J=7.3Hz, 2H), 1.19-1.68(m,6H)。
Intermediate 118 (0.1mmol) and embodiment 15 (0.1mmol) are dissolved in 1mL butanol/water (v/v=1:1), successively The solution of aqueous solution (6mg/600 μ L), cupric sulfate pentahydrate that vitamine C sodium is added also (10mg/800 μ L), then reacts for 45 DEG C, It is detected after 8h through LC-MS, display raw material fundamental reaction is complete, stops heating, adds water 4mL, be extracted with ethyl acetate 3 times, merges Ethyl acetate layer is concentrated under reduced pressure, and obtains title compound after purification through silica gel column chromatography (DCM/MeOH=10:1), yellow solid is received Rate: 148-150 DEG C of 30%, mp,1H-NMR(300MHz,DMSO-d6)δ14.31(s,1H),11.82(s,1H),8.22(s, 1H), 7.96 (s, 1H), 6.40 (s, 1H), 6.33 (s, 1H), 4.86 (s, 2H), 4.40 (t, J=6.0Hz, 2H), 4.20-4.31 (m, 1H), 4.00-4.13 (m, 1H), 3.84-3.91 (m, 1H), 3.77 (s, 2H), 3.46-3.52 (m, 2H), 3.09 (t, J= 7.2Hz, 2H), 2.73-2.89 (m, 1H), 2.78 (dd, J=12.1,4.7Hz, 1H), 2.55 (d, J=12.5Hz, 1H), 2.10 (s, 3H), 2.04 (t, J=7.5Hz, 2H), 1.96 (s, 3H), 1.69-1.78 (m, 1H), 1.55-1.64 (m, 2H), 1.42- 1.50 (m, 2H), 1.33-1.40 (m, 1H), 1.15-1.30 (m, 4H), 1.09 (d, J=6.9Hz, 3H), 0.85 (t, J= 7.3Hz,6H).13C-NMR(125MHz,DMSO-d6)δ207.0,206.8,173.0,163.2,160.2,159.9,158.6, 158.3,157.6,142.5,125.4,111.8,110.8,109.7,105.3,104.9,99.9,67.7,61.5,59.7, 55.8,49.3,45.7,44.7,35.5,28.6,28.5,27.0,25.6,17.2,17.1,14.6,14.0,12.3,10.1, 9.0.HRMS calcd for C39H53O10N6S[M+H]+:797.35384；found:797.354553.
114 N- of embodiment (2- (4- ((3- (2- methylbutyryl) -3,5- dihydroxy -6- methyl -4- (tri- hydroxyl of 2,4,6- Base -3- methyl -5- (2- methylbutyryl) phenyl) phenoxy group) methyl) -1H-1,2,3- triazol-1-yl) ethyl) -5- ((3S, 4S, 6R) -2- hexahydro -1H- [3,4-d] imidazol-4 yl) pentanamide
Referring to embodiment 113 title compound, white solid, yield 40%, mp 148-149 DEG C,1H-NMR (300MHz,DMSO-d6)δ8.21(s,1H),7.97(s,1H),6.40(s,1H),6.34(s,1H),4.83(s,2H),4.43 (t, J=6.0Hz, 2H), 4.22-4.35 (m, 1H), 4.11-4.13 (m, 1H), 3.81 (s, 2H), 3.66 (s, 3H), 3.46- 3.52 (m, 2H), 3.06 (t, J=7.2Hz, 2H), 3.00 (t, J=6.9Hz, 2H), 2.73-2.82 (m, 1H), 2.78 (dd, J =12.1,4.7Hz, 1H), 2.55 (d, J=12.5Hz, 1H), 2.07 (s, 3H), 2.04 (t, J=7.5Hz, 2H), 2.01 (s, 3H), 1.54-1.66 (m, 4H), 1.35-1.56 (m, 2H), 1.23-1.35 (m, 4H), 0.91 (t, J=7.2Hz, 3H), 0.85 (t, J=7.2Hz, 6H)13C-NMR(125MHz,DMSO-d6)δ206.4,206.2,172.6,162.8,160.5,160.3, 159.2,159.1,158.9,157.1,142.2,125.0,110.9,110.5,109.9,109.6,109.2,108.6,67.3, 61.6,61.1,59.3,55.5,48.9,48.7,44.4,44.1,35.1,28.2,28.1,25.2,17.7,17.7,16.5, 13.8,13.7,9.7,9.3.HRMS calcd for C39H53O10N6S[M+H]+:797.35384；found:797.35406.
The chloro- 5- of 115 7- of embodiment ((3- ethyl -5,7- dihydroxy -8- methyl -4- chroman -6- base) methyl) -6,8- two Hydroxyl -1,3,3a, 9a- tetrahydro cyclopentyl alkene [b] chroman -9 (2H)-alkene
Chloro- 6,8- dihydroxy -1,3,3a, 9a- tetrahydro cyclopentyl alkene [b] chroman -9 (2H) of 7--alkene (119) and the chloro- 6,8- of 5- Dihydroxy -1,3,3a, 9a- tetrahydro cyclopentyl alkene [b] chroman -9 (2H)-alkene (120)
Intermediate 119 is obtained referring to the synthetic method of intermediate 48, yellow solid, yield 42.9%,1H-NMR (400MHz,Acetone)δ12.93(s,1H),11.60(s,1H),6.06(s,1H),4.92-4.97(m,1H),2.77-2.84 (m,1H),2.03-2.12(m,1H),1.93-2.03(m,2H),1.82-1.89(m,1H),1.69-1.82(m,2H)；And it is intermediate Body 120, yellow solid, yield 35.6%,1H-NMR(400MHz,Acetone-d6)δ12.29(s,1H),11.56(s,1H), 6.08(s,1H),5.00-5.08(m,1H),2.78-2.88(m,1H),1.95-2.13(m,3H),1.71-1.95(m,3H)。
Referring to the synthetic method of embodiment 24, title compound is obtained by intermediate 76 and intermediate 119, yellow solid, Yield 25.4%, mp:187-190 DEG C.1H-NMR(400MHz,DMSO-d6) δ 12.89 (s, 1H), 12.56 (d, J=7.6Hz, 1H), 4.68-4.77 (m, 1H), 4.44 (dd, J=11.3Hz, 4.3Hz, 1H), 4.22 (dd, J=10.9Hz, 7.8Hz, 1H), 3.71-3.76(m,2H),2.65-2.75(m,1H),2.54-2.59(m,1H),1.92-2.14(m,2H),1.91(s,3H), 1.77-1.85 (m, 1H), 1.55-1.77 (m, 4H), 1.29-1.55 (m, 1H), 0.95 (t, J=7.0Hz, 3H)13C-NMR (100MHz,DMSO-d6)δ199.5,198.8,163.6,159.7,157.9,157.9,157.8,157.1,122.5,108.4, 107.4,102.3,101.2,100.3,99.9,83.0,69.7,48.9,45.8,32.5,28.2,22.7,20.2,17.2, 11.7,8.6.ESI-MS:calcd for C25H25BrO8[M+H]+:533.07；found,533.45.
The chloro- 7- of 116 5- of embodiment ((3- ethyl -5,7- dihydroxy -8- methyl -4- chroman -6- base) methyl) -6,8- two Hydroxyl -1,3,3a, 9a- tetrahydro cyclopentyl alkene [b] chroman -9 (2H)-alkene
Referring to the synthetic method of embodiment 24, title compound is obtained by intermediate 76 and intermediate 120, yellow solid, Yield 22.7%, mp 198-201 DEG C.1H-NMR(400MHz,DMSO-d6)δ12.73(s,1H),12.62(s,1H),4.98- 5.00 (m, 1H), 4.46 (dd, J=11.3Hz, 4.6Hz, 1H), 4.22 (dd, J=11.3Hz, 8.0Hz, 1H), 3.76 (s, 2H),2.77-2.83(m,1H),2.57-2.62(m,1H),1.93-2.17(m,3H),1.92(s,3H),1.87-1.89(m, 1H), 1.67-1.82 (m, 3H), 1.45-1.55 (m, 1H), 0.95 (t, J=7.5Hz, 3H)13C-NMR(100MHz,DMSO- d6)δ199.7,198.9,163.0,160.8,159.9,159.6,158.1,155.0,108.6,106.7,102.4,101.5, 100.3,99.4,84.0,69.7,49.1,45.6,32.7,28.2,22.6,20.0,16.4,11.7,8.6.ESI-MS:calcd for C25H25BrO8[M+H]+:533.07；found,533.32.
The chloro- 8- of 117 6- of embodiment ((3- ethyl -5,7- dihydroxy -8- methyl -4- chroman -6- base) methyl -5,7- dihydroxy Base -2- methyl -4H- chroman-4-on
2,4,6- trihydroxy-acetophenone (121)
Intermediate 121 is obtained referring to the synthetic method of intermediate 3, yellow solid, yield 85%,1H-NMR(400MHz, DMSO-d6)δ12.41(s,2H),11.55(s,1H),10.92(s,1H),5.88(s,2H),2.52(s,3H)。
5,7- dihydroxy -2- methyl -4H- chroman-4-on (122)
Intermediate 121 (12.5mmol) is dissolved in the aceticanhydride of 10mL, is subsequently added into sodium acetate (37.5mmol), and reflux is anti- 2h is answered, cooling, 30mL water is added into, and ethyl acetate extraction is concentrated under reduced pressure.Solid after concentration is dissolved in sodium carbonate (62.5mmol) Aqueous solution in (30mL), flow back 3h, be concentrated under reduced pressure, after silica gel column chromatography (ethyl acetate/petroleum ether=1:4) pale yellow colored solid Body 122, yield: 66.7%,1H-NMR(400MHz,DMSO-d6)δ12.81(s,1H),10.77(s,1H),6.32(s,1H), 6.16(s,1H),6.17(s,1H),2.34(s,3H)。
The bromo- 5,7- dihydroxy -2- methyl -4H- chroman-4-on (123) of 6-
Intermediate 122 (1.6mmol) is dissolved in 15mL tetrahydrofuran, and NBS (1.7mmol) is added portionwise under room temperature, after Continuous reaction 1h, is concentrated under reduced pressure, faint yellow solid 123 is obtained after C18 silica gel column chromatography (water/methanol=95:5-0:100), yield: 55.1%,1H-NMR(400MHz,DMSO-d6)δ12.89(s,1H),11.63(s,1H),6.40(s,1H),6.28(s,1H), 2.41(s,3H)。
Referring to the synthetic method of embodiment 24, title compound is obtained by intermediate 76 and intermediate 123, yellow solid, Yield 30.8%, mp197-200 DEG C.1H-NMR(400MHz,DMSO-d6)δ13.27(s,1H),12.69(s,1H),6.20(s, 1H), 4.45 (dd, J=11.3Hz, 4.4Hz, 1H), 4.21 (dd, J=11.2Hz, 8.0Hz, 1H), 3.83 (s, 2H), 2.53- 2.60 (m, 1H), 2.38 (s, 3H), 1.90 (s, 3H), 1.71-1.79 (m, 1H), 1.38-1.59 (m, 1H), 0.95 (t, J= 7.4Hz,3H).13C-NMR(100MHz,DMSO-d6)δ199.3,181.9,167.5,164.4,159.7,158.3,158.1, 152.7,112.2,108.4,106.8,103.5,102.6,101.1,88.0,69.7,45.6,20.4,20.1,17.1,11.8, 8.6.ESI-MS:calcd for C23H21BrO8[M+H]+:505.04；found,505.58.
The bromo- 2- ethyl -8- of 118 6- of embodiment ((3- ethyl -5,7- dihydroxy -8- methyl -4- chroman -6- phenyl) first Base) -5,7- dihydroxy -2- methyl chroman-4-on
Referring to the synthetic method of embodiment 1, benzaldehyde is added, title compound is obtained by intermediate 75 and intermediate 54a, Yellow solid, yield 22.8%, mp 195-197 DEG C.1H-NMR(400MHz,DMSO-d6)δ7.30(s,1H),7.26-7.29 (m,1H),7.21(s,1H),7.14(s,1H),7.10-7.14(m,1H),5.48(s,1H),4.07(s,1H),3.82(s, 1H),3.69(s,1H),2.85(s,1H),2.55(s,1H),2.16(s,3H),1.82(s,2H),1.59(s,2H),1.41(s, 3H), 0.92 (d, J=16.0Hz, 6H)13C-NMR(100MHz,DMSO-d6)δ205.5,196.2,163.4,162.5, 162.2,161.7,156.2,156.0,143.7,128.8,127.6,126.8,110.1,106.4,105.9,103.1, 101.6,87.6,75.3,70.5,49.6,47.4,32.7,31.3,25.922.8,11.7,9.9,7.8。ESI-MS:calcd for C31H31BrO8[M-H]+:609.12；found,609.53.
Embodiment 119 2 (3- ethyl -5,7- dihydroxy -8- methyl chroman-4-on) -6,6 '-methylbenzenes
Referring to the synthetic method of embodiment 118, title compound is obtained by intermediate 75, yellow solid, yield 39.8%, mp 167-169℃。1H-NMR(400MHz,DMSO-d6)δ13.07(s,1H),13.05(s,1H),9.69(br,2H),7.25 (t, J=7.5Hz, 2H), 7.15 (t, J=7.2Hz, 1H), 6.98 (d, J=8.1Hz, 2H), 6.51 (s, 1H), 4.50-4.56 (m,2H),4.24-4.33(m,2H),2.63-2.70(m,2H),1.93(s,6H),1.74-1.79(m,2H),1.47-1.54 (m,2H),0.94-0.99(m,6H).13C-NMR(100MHz,DMSO-d6)δ200.1,162.7,159.8,158.8,141.7, 128.7,127.2,126.0,108.5,103.3,101.8,69.8,45.6,33.4,19.8,11.7,8.6.ESI-MS:calcd for C31H32O8[M-H]+:531.21；found,531.47.
The bromo- 2- ethyl -8- of 120 6- of embodiment ((3- ethyl -5,7- dihydroxy -8- methyl -4- chroman -6- (4- fluorobenzene Base)) methyl) -5,7- dihydroxy -2- methyl chroman-4-on
Referring to the synthetic method of embodiment 1,4- fluorobenzaldehyde is added, title compound is by intermediate 75 and intermediate 54a It obtains, yellow solid, yield 21.6%, mp 201-203 DEG C.1H-NMR(400MHz,DMSO-d6)δ7.20-7.24(m,1H), 7.17-7.19(m,1H),7.15-7.17(m,1H),7.10-7.13(m,1H),5.48(s,1H),4.07(s,1H),3.82(s, 1H), 3.69 (s, 1H), 2.72 (d, J=18.4Hz, 2H), 2.16 (s, 3H), 1.82 (s, 2H), 1.59 (s, 2H), 1.41 (s, 3H), 0.92 (d, J=16.0Hz, 6H)13C-NMR(100MHz,DMSO-d6)δ205.5,196.2,163.4,162.8, 162.5,162.2,161.7,156.2,156.0,136.9,128.6,115.7,110.1,106.4,105.9,103.1, 101.6,87.6,75.3,70.5,49.6,47.4,32.7,31.3,25.9,22.8,11.7,9.9,7.8。ESI-MS:calcd for C31H30BrFO8[M-H]+:627.11；found,627.33.
Embodiment 121 2 (3- ethyl -5,7- dihydroxy -8- methyl chroman-4-on) -6,6 '-methyl (4- fluorobenzene)
Referring to the synthetic method of embodiment 120, title compound is obtained by intermediate 75, yellow solid, yield 18.6%, mp 198-200℃。1H-NMR(400MHz,DMSO-d6) δ 7.22 (dd, J=5.1,2.6Hz, 1H), 7.19-7.21 (m, 1H), 7.17-7.19(m,1H),7.14-7.16(m,1H),5.48(s,1H),4.07(s,2H),3.82(s,2H),3.69(s,2H), 2.16(s,6H),1.59(s,4H),0.94(s,6H).13C-NMR(100MHz,DMSO-d6)δ205.5,163.4,162.9, 161.7,156.2,136.9,128.6,115.7,106.4,105.9,101.6,70.5,49.6,33.1,22.8,11.7,9.9。 ESI-MS:calcd for C31H31FO8[M-H]+:549.20；found,549.45.
122 8- acetyl group -6- of embodiment (3- bytyry -2,6- dihydroxy -4- methoxyl group -5- aminomethyl phenyl) -3- is fluoro- 5,7- dihydroxy -4- methyl -2H- chromane-2-one
The fluoro- 5,7- dihydroxy -4- methyl -2H- chromane-2-one (124) of 3-
Phloroglucin (0.1mol) and 2- acetyl fluoride ethyl acetate (0.1mol) are dissolved in 150ml dehydrated alcohol, and trifluoro is added Change borate ether solution (0.3mol), back flow reaction, LC-MS tracing detection, be concentrated under reduced pressure, filtering, obtained solid is successively with saturation Sodium bicarbonate aqueous solution, water washing, final yellow solid 124, yield 84.0%.1H-NMR(400MHz,DMSO-d6)δ 10.59 (s, 1H), 10.23 (s, 1H), 6.32 (d, J=2.4Hz, 1H), 6.21 (d, J=2.4Hz, 1H), 2.45 (s, 3H).
The fluoro- 5,7- dihydroxy -4- methyl -2H- chromane-2-one (125) of 8- acetyl group -3-
Intermediate 124 (14mmol) is mixed in 5mL nitromethane, is stirred at room temperature down and is carefully added into alchlor (68mmol) continues stirring to reaction mixture in solution state, is slowly added dropwise acetic anhydride (15mmol), 100 DEG C of reaction 1h, cold But, 4M HCl (30mL) and ethyl acetate (100mL) are added thereto, is vigorously stirred, extracts, dry, concentration, residual solid is used Ethyl acetate washs to obtain white solid 125, yield 56.3%.1H-NMR(400MHz,DMSO-d6)δ12.97(s,1H), 11.75(s,1H),6.37(s,1H),2.66(s,3H)。
Referring to the synthetic method of embodiment 24, title compound is obtained by intermediate 34 and intermediate 125, yellow solid, Yield 21.6%, mp202-204 DEG C.1H-NMR(400MHz,CDCl3)δ16.23(s,1H),15.97(s,1H),10.53(s, 1H), 9.13 (s, 1H), 3.89 (s, 2H), 3.73 (s, 3H), 3.10 (t, J=7.3Hz, 2H), 2.91 (s, 3H), 2.63 (d, J =3.4Hz, 3H), 2.11 (s, 3H), 1.72-1.77 (m, 2H), 1.00 (t, J=7.4Hz, 3H)13C-NMR(100MHz, CDCl3)δ207.2,203.9,163.5,161.6,160.6,159.6,153.5,153.2,152.7,134.9,134.8, 112.5,110.5,108.2,107.9,103.6,103.2,77.3,77.0,76.7,61.6,44.3,33.2,18.1,16.2, 14.4,13.9,9.2.HRMS calcd for C25H25FO9[M-H]+:487.1404；found,487.1418.
The bromo- 6- of 123 8- of embodiment (3- bytyry -2,6- dihydroxy -4- methoxyl group -5- aminomethyl phenyl) -5,7- dihydroxy Base -4- methyl -2H- chromane-2-one
5,7- dihydroxy -4- methyl -2H- chromane-2-one (126)
Intermediate 126, yellow solid, yield 75.0% are obtained referring to the synthetic method of intermediate 124.1H-NMR (400MHz,DMSO-d6) δ 10.50 (s, 1H), 10.28 (s, 1H), 6.24 (d, J=2.4Hz, 1H), 6.15 (d, J=2.4Hz, 1H),5.82(s,1H),2.47(s,3H)。
The bromo- 5,7- dihydroxy -4- methyl -2H- chromane-2-one (127) of 8-
Intermediate 127, yellow solid, yield 69.2% are obtained referring to the synthetic method of intermediate 123.1H-NMR (400MHz,Acetone-d6)δ9.20(s,2H),6.54(s,1H),5.97(s,1H),2.61(s,3H)。
Referring to the synthetic method of embodiment 24, title compound is obtained by intermediate 76 and intermediate 127, yellow solid, Yield 15.3%, mp 195-197 DEG C.1H-NMR(400MHz,DMSO-d6)δ12.62(s,1H),9.51(s,3H),5.96(s, 1H), 4.47 (dd, J=11.1Hz, 3.9Hz, 1H), 4.19-4.26 (m, 1H), 3.96 (s, 2H), 2.56 (d, J=19.6Hz, 4H), 1.92 (s, 3H), 1.73 (dd, J=13.5Hz, 6.3Hz, 1H), 1.46-1.53 (m, 1H), 0.95 (t, J=7.3Hz, 3H).13C-NMR(100MHz,DMSO-d6)δ199.0,159.4,159.0,157.6,154.4,152.5,150.9,110.3, 108.4,106.1,104.2,101.9,100.8,98.2,69.1,45.0,23.9,19.4,17.0,11.2,8.1.ESI-MS: calcd for C23H21BrO8[M-H]+:503.04；found,503.23.
124 8- acetyl group -6- of embodiment (3- bytyry -2,6- dihydroxy -4- methoxyl group -5- aminomethyl phenyl) -4- second The fluoro- 5,7- dihydroxy -2H- chromane-2-one of base -3-
The fluoro- 5,7- dihydroxy -4- ethyl -2H- chromane-2-one (128) of 3-
Intermediate 128, yellow solid, yield 91.0% are obtained referring to the synthetic method of intermediate 124.1H-NMR (400MHz,DMSO-d6) δ 10.64 (s, 1H), 10.29 (s, 1H), 6.33 (d, J=2.4Hz, 1H), 6.22 (d, J=2.4Hz, 1H), 2.96-2.99 (m, 2H), 1.18 (t, J=7.2Hz, 3H).
The fluoro- 5,7- dihydroxy -4- ethyl -2H- chromane-2-one (129) of 8- acetyl group -3-
Intermediate 129, yellow solid, yield 67.1% are obtained referring to the synthetic method of intermediate 125.1H-NMR (400MHz,DMSO-d6)δ12.87(s,1H),11.75(s,1H),6.38(s,1H),2.98-3.06(m,2H),2.66(s, 3H), 1.20 (t, J=7.4Hz, 3H).
Referring to the synthetic method of embodiment 24, title compound is obtained by intermediate 34 and intermediate 129, yellow solid, Yield 31.3%, mp204-206 DEG C.1H-NMR(400MHz,CDCl3)δ16.23(s,1H),15.99(s,1H),10.59(s, 1H), 9.16 (s, 1H), 3.90 (s, 2H), 3.73 (s, 3H), 3.14-3.17 (m, 2H), 3.10 (t, J=7.3Hz, 2H), 2.91 (s, 3H), 2.11 (s, 3H), 1.72-1.77 (m, 2H), 1.27 (t, J=7.4Hz, 3H), 1.00 (t, J=7.4Hz, 3H)13C- NMR(100MHz,CDCl3)δ207.3,204.0,163.4,161.6,161.1,161.0,160.6,159.6,153.6, 153.3,153.3,153.2,142.6,140.5,140.4,140.2,112.5,110.6,108.2,107.9,103.7, 102.6,61.6,44.2,33.3,20.5,20.4,18.1,16.3,14.0,13.9,9.2.HRMS calcd for C26H27FO9 [M-H]+:501.1561；found,501.1579.
125 8- acetyl group -6- of embodiment (3- bytyry -2,6- dihydroxy -4- methoxyl group -5- aminomethyl phenyl) -3- is fluoro- 5,7- dihydroxy -4- propyl -2H- chromane-2-one
The fluoro- 5,7- dihydroxy -4- propyl -2H- chromane-2-one (130) of 3-
Intermediate 130, yellow solid, yield 88.0% are obtained referring to the synthetic method of intermediate 124.1H-NMR (400MHz,DMSO-d6) δ 10.63 (s, 1H), 10.27 (s, 1H), 6.31 (d, J=2.4Hz, 1H), 6.21 (d, J=2.4Hz, 1H), 2.94 (dt, J=3.3Hz, 8.1Hz, 2H), 1.57-1.62 (m, 2H), 0.94 (t, J=7.2Hz, 3H).
The fluoro- 5,7- dihydroxy -4- propyl -2H- chromane-2-one (131) of 8- acetyl group -3-
Intermediate 131, yellow solid, yield 62.1% are obtained referring to the synthetic method of intermediate 125.1H-NMR (400MHz,DMSO-d6)δ12.89(s,1H),11.74(s,1H),6.35(s,1H),2.90-3.02(m,2H),2.66(s, 3H), 1.55-1.67 (m, 2H), 0.97 (t, J=7.3Hz, 3H).
Referring to the synthetic method of embodiment 24, title compound is obtained by intermediate 34 and intermediate 131, yellow solid, Yield 35.6%, mp207-209 DEG C.1H-NMR(400MHz,CDCl3)δ16.24(s,1H),15.98(s,1H),10.58(s, 1H), 9.17 (s, 1H), 3.89 (s, 2H), 3.74 (s, 3H), 3.10 (t, J=7.3Hz, 4H), 2.92 (s, 3H), 2.12 (s, 3H),1.64-1.77(m,4H),0.98-1.05(m,6H).13C-NMR(100MHz,CDCl3)δ207.3,204.0163.4, 161.7,161.1,161.1,160.6,159.6,153.6,153.3,153.2,142.8,140.4,138.8,138.7, 112.5,110.7,108.3,107.9,103.7,102.7,61.6,44.2,33.3,28.7,28.6,22.8,18.1,16.3, 14.1,13.9,9.2.HRMS calcd for C27H29FO9[M-H]+:515.1717；found,515.1722.
The bromo- 6- of 126 8- of embodiment (3- bytyry -2,6- dihydroxy -4- methoxyl group -5- aminomethyl phenyl) fluoro- 5,7- of -3- Dihydroxy -4- methyl -2H- chromane-2-one
The fluoro- 5,7- dihydroxy -4- methyl -2H- chromane-2-one (132) of the bromo- 3- of 8-
Intermediate 132, yellow solid, yield 72.3% are obtained referring to the synthetic method of intermediate 123.1H-NMR (400MHz,Acetone-d6)δ11.22(s,1H),10.97(s,1H),6.72(s,1H),2.51(s,3H)。
Referring to the synthetic method of embodiment 24, title compound is obtained by intermediate 34 and intermediate 132, yellow solid, Yield 21.5%, mp183-186 DEG C.1H-NMR(400MHz,CDCl3)δ16.04(s,1H),8.98(s,2H),3.69(s,2H), 3.62(s,3H),2.98(s,2H),2.54(s,3H),1.94(s,3H),1.60-1.64(m,2H),0.92(s,3H).13C-NMR (100MHz,CDCl3)δ203.5,160.4,160.0,154.9,154.6,148.4,114.4,112.8,110.8,108.1, 104.2,100.0,61.4,43.0,19.7,18.7,14.4,14.3,14.2,9.9.HRMS calcd for C23H22BrFO8 [M-H]+:523.0404；found,523.0408.
127 4- acetyl group -2- of embodiment (3- bytyry -2,6- dihydroxy -4- methoxyl group -5- aminomethyl phenyl) -1,3- two Hydroxyl -7,8,9,10- tetrahydro -6H- benzo [c] chroman -6- ketone
1,3- dihydroxy -7,8,9,10- tetrahydro -6H- benzo [c] chroman -6- ketone (133)
Intermediate 133, yellow solid, yield 83.0% are obtained referring to the synthetic method of intermediate 124.1H-NMR (400MHz,DMSO-d6) δ 10.34 (s, 1H), 10.08 (s, 1H), 6.24 (d, J=2.4Hz, 1H), 6.13 (d, J=2.4Hz, 1H),3.00-3.03(m,2H),2.31-2.33(m,2H),1.61-1.64(m,4H)。
4- acetyl group -1,3- dihydroxy -7,8,9,10- tetrahydro -6H- benzo [c] chroman -6- ketone (134)
Intermediate 134, yellow solid, yield 72.6% are obtained referring to the synthetic method of intermediate 125.1H-NMR (400MHz,DMSO-d6)δ13.29(s,1H),11.55(s,1H),6.23(s,1H),2.95-3.05(m,2H),2.68(s, 3H),2.34-2.41(s,2H),1.62-1.70(s,4H)。
Referring to the synthetic method of embodiment 24, title compound is obtained by intermediate 34 and intermediate 134, yellow solid, Yield 29.4%, mp210-212 DEG C.1H-NMR(400MHz,CDCl3)δ16.27(s,1H),15.87(s,1H),10.35(s, 1H), 9.27 (s, 1H), 3.87 (s, 2H), 3.72 (s, 3H), 3.15 (s, 2H), 3.09 (t, J=7.3Hz, 2H), 2.92 (s, 3H), 2.53 (s, 2H), 2.11 (s, 3H), 1.70-1.79 (m, 6H), 1.00 (t, J=7.4Hz, 3H)13C-NMR(100MHz, CDCl3)δ207.1,204.1,162.9,161.7,161.3,160.5,159.9,159.6,154.6,150.9,119.5, 112.4,109.5,108.5,107.8,104.5,103.4,61.6,44.2,33.2,30.4,24.5,22.3,21.0,18.1, 16.1,14.0,9.2.HRMS calcd for C28H30O9[M-H]+:509.1812；found,509.1821.
128 8- acetyl group -6- of embodiment ((3- ethyl -5,7- dihydroxy -8- methyl -4- chroman -6- base) methyl) -3- Fluoro- 5,7- dihydroxy -4- methyl -2H- chromane-2-one
Referring to the synthetic method of embodiment 24, title compound is obtained by intermediate 76 and intermediate 125, yellow solid, Yield 21.6%, mp198-200 DEG C.1H-NMR(400MHz,DMSO-d6)δ14.33(s,1H),12.80(s,1H),8.78(s, 2H), 4.46 (dd, J=11.2Hz, 4.4Hz, 1H), 4.22 (dd, J=11.2Hz, 8.1Hz, 1H), 3.82 (s, 2H), 2.71 (s, 3H), 2.58 (d, J=3.1Hz, 4H), 1.92 (s, 3H), 1.69-1.78 (m, 1H), 1.44-1.53 (m, 1H), 0.95 (t, J=7.4Hz, 3H)13C-NMR(100MHz,DMSO-d6)δ202.6,199.7,164.9,163.3,159.3,158.2, 153.7,153.3,152.8,142.3,140.0,135.3,135.3,111.5,106.5,103.0,102.7,102.4,101.3, 69.7,45.6,33.3,20.0,16.6,14.6,14.6,11.7,8.6.HRMS calcd for C25H23FO9[M-H]+: 485.1248；found,485.1262.
The bromo- 6- of 129 8- of embodiment ((3- ethyl -5,7- dihydroxy -8- methyl -4- chroman -6- base) methyl) -3- fluoro- 5, 7- dihydroxy -4- methyl -2H- chromane-2-one
Referring to the synthetic method of embodiment 24, title compound is obtained by intermediate 76 and intermediate 132, yellow solid, Yield 19.8%, mp190-192 DEG C.1H-NMR(400MHz,DMSO-d6) δ 13.50 (s, 1H), 4.47 (dd, J=11.3Hz, 4.5Hz, 1H), 4.23 (dd, J=11.3Hz, 7.9Hz, 1H), 3.80 (s, 2H), 2.58-2.63 (m, 1H), 2.55 (t, J= 4.3Hz, 3H), 1.91 (s, 3H), 1.72-1.78 (m, 1H), 1.47-1.53 (m, 1H), 0.96 (t, J=7.5Hz, 3H)13C- NMR(100MHz,DMSO-d6)δ199.1,158.5,157.9,154.5,154.2,147.8,142.1,139.8,134.9, 134.7,130.1,114.0,106.9,103.7,102.6,100.5,90.0,69.7,45.3,20.1,18.3,14.4,14.3, 11.8,8.7.HRMS calcd for C23H20BrFO8[M-H]+:521.0247；found,521.0253.
130 8- acetyl group -6- of embodiment ((the bromo- 2- ethyl -5,7- dihydroxy -2- methyl -4- chroman -8- base of 6-) first Base) the fluoro- 5,7- dihydroxy -4- methyl -2H- chromane-2-one of -3-
Referring to the synthetic method of embodiment 24, title compound is obtained by intermediate 54a and intermediate 125, yellow solid, Yield 18.1%, mp 209-211 DEG C.1H-NMR(400MHz,DMSO-d6)δ14.33(s,1H),12.91(s,1H),3.75- 3.84 (m, 2H), 2.82 (d, J=17.2Hz, 1H), 2.70 (s, 3H), 2.58-2.62 (m, 4H), 1.64-1.69 (m, 2H), 1.22 (s, 3H), 0.86 (t, J=7.4Hz, 3H)13C-NMR(100MHz,DMSO-d6)δ201.6,196.5,165.3, 164.7,158.1,157.8,153.9,153.6,153.5,141.9,139.5,136.4,136.3,111.7,108.6, 102.8,101.8,101.1,90.8,81.4,44.6,33.2,32.3,23.3,18.1,14.6,8.2.ESI-MS:calcd for C25H22BrFO9[M+H]+:563.04；found,563.21.
The external BCG and Mtb pH of embodiment 131IBDetection
1) using the BCG vaccine (BCG) or mycobacterium tuberculosis (Mtb) (BCG- of transfection green fluorescent protein (pHGFP) pHGFP or H37Rv-pHGFP), inoculum (OD is added in 96 orifice plates580=0.2), phosphate-citrate salts-Tai Luo The untested compound of sand pool buffer and various concentration.After a certain period of time, read 395nm respectively, under 475nm excitation wavelength and Fluorescent value under 510nm wavelength of transmitted light is calculated referring to corresponding curve by the ratio (395nm/475nm) of fluorescent value pHIBValue.If pHIB﹤ 6.0, then be accredited as reactive compound.
2) using DMSO as negative control, using natural agrimophol as positive control, evaluation compound first is in single high dose (12.5 μM) are to the pH of BCGIBInhibitory activity.
3) it for reactive compound, then reduces compound concentration and carries out multi-dose screening, so that finding compound can By the pH of BCG or MtbIBIt is down to 6.0 Cmin.
The preferable activity for reducing pH in bacterium is illustrated by embodiment compound it can be seen from the data of table 1, it is especially fragrant The analog of legumin ring.
Table 1: compound reduces the Cmin below of pH to 6.0 in BCG Mtb bacterium
ND=is not detected
The detection of 132 Vitro hepatic Microsomal Stability of embodiment
300 μ L blood plasma equivalent are pipetted into 1.1mL pipe (n=1)；37 DEG C preincubate 15 minutes, be subsequently added into 3.0 μ L Positive control totokaine (100 μM of in DMSO) and test compound (1mM in acetonitrile)；In 0min, 5min, 15min, The time point of 30min, 1h and 2h respectively take out the sample of 200 μ L in each pipe, and 200 μ L are added is quenched solution, are acutely vortexed 1min；Then 100 supernatants are pipetted into 0.65mL pipe with 4000rpm Centrifuge A sample 15min at 4 DEG C；Lcms analysis.
Table 2 as the result is shown relative to the hepatomicrosome of mouse as a result, part of compounds is shown in the hepatomicrosome of people Preferable metabolic stability, reason should be the difference between animal species.Metabolic stability is coumarin analogue (embodiment Compound 122) > linear structure chemical combination object (embodiment compound 3 and 5) > chromanone structural compounds (embodiment compound 69). Analysis simultaneously finds agrimophol unsaturated ring and chromanone is main metabolism site.The embodiment as the result is shown of same table 3 Closing object main metabolic enzyme in people's hepatomicrosome is cytochrosome P-450 isoforms 3A4.
Table 2: metabolic stability evaluation of the compound in people and rat hepatic microsome
ND=is not detected
Table 3: cytochrosome P-450 isoforms evaluation of the embodiment compound 122 in people's hepatomicrosome
The compounds of this invention long half time in people's hepatomicrosome as a result, metabolic stability are high.
The evaluation of 133 HepG2 cellulotoxic experiment of embodiment
By HepG2 cell inoculation to RPMI1640 culture medium (100 μ L, 5%FBS and the 2mM in 96 hole microtiter plates L-Glutamine) in and be incubated for for 24 hours.The compound of addition various concentration and then incubation 48h (37 DEG C, 5%CO2, 95% is empty Gas and 100% relative humidity), the cold TCA (10%TCA) of 50 μ L is added, continues to be incubated for 1h at 4 DEG C, discards supernatant liquid, be washed with water It washs plate 5 times and is air-dried, Sulforhodamine B solution (100 μ L, 0.4% (v/v) in 1%acetic are added Acid), continuing to be incubated for 10min in room temperature, dyeing is washed 5 unbonded dyestuffs of removing with 1% acetic acid and is air-dried, It is then dissolved with 10mM trizma and Multiscan Spectrum is used to read the absorbance at 515nm.The inhibition of cell growth Percentage calculates as follows: [(C-T)/C] * 100, C is control group growth number, and T is testing drug group growth number.The result of Fig. 1 is aobvious Show activity and the preferable compound 122 of metabolic stability while also there is lower cytotoxicity, SI value with higher.Table 4 is aobvious The EC of agrimophol and activity and the preferable embodiment compound 122 and 128 of metabolic stability is shown50,LD50With the calculating knot of SI value Fruit, wherein SI is selectivity index, and value is LD50/EC50.Calculated result shows the SI value of embodiment compound 122 and 128 Much larger than 10, show that the compound of the embodiment of the present invention has lower cytotoxicity.
Table 4: the EC of agrimophol and embodiment compound 122 and 12850,LD50With the calculating of SI value
Embodiment number EC50(μM) LD50(μM) SI
Agrimophol 0.9669 3.383 3.5
122 0.06502 15.69 241.31
128 0.0618 4.375 70.79
The external Mtb of embodiment 134 and the MDR-Mtb and XDR-Mtb that are clinically separated existence activity rating
Wild type Mtb: the culture medium of wild type Mtb is washed 2 times with Pcit-Tyl-4.5, is centrifuged 10 minutes (120g), is connect Dilution OD580Value is 0.1, pipettes 200 μ L and is added in 96 orifice plates, and the compound of various concentration is added, and 37 DEG C are incubated for 6 days, PBS is washed 2 times, collects Mtb, bed board (7H11agar), and 37 DEG C of incubations count.With DMSO and natural agrimophol respectively as yin Property and positive control.
MDR-Mtb and XDR-Mtb: the bacterial strain being clinically separated is washed 2 times with Pcit-Tyl-4.5, is centrifuged 10 minutes (120g), then dilutes OD580Value is 0.2, pipettes 200 μ L and is added in 96 orifice plates, is added the compound of various concentration, 37 DEG C It is incubated for 6 days, PBS is washed 2 times, collects bacterial strain, and bed board (7H11agar), 37 DEG C are incubated for 3 days, and fluorescence indicator 9,9- diformazan is added Base -2- nitro -7- propyl -10,11- dihydrofuran [2,3-f] pyrans [2,3-h] chroman -5 (9H) -one, in exciting light 390nm Fluorescent value is detected under transmitting light 470nm wavelength, calculates inhibiting rate.
Embodiment compound 122 can make Colony Forming Unit (CFU) to reduce by 1.5 numbers to Fig. 2 at 0.78 μM as the result is shown Magnitude, 3.125 μM can make Colony Forming Unit (CFU) to reduce by 3 orders of magnitude.And agrimophol and embodiment compound 128 exist 3.125 μM can make Colony Forming Unit (CFU) to reduce by 1 order of magnitude.Embodiment compound 122 and agrimophol inhibit simultaneously The MIC of MDR-Mtb growth90Value is the MIC of 1.56 μM and inhibition XDR-Mtb growth90Value is 6.25 μM.
The compounds of this invention activity with higher for inhibiting Mtb growth and inhibition MDR-Mtb and XDR-Mtb are raw as a result, Long activity.
In the description of this specification, reference term " one embodiment ", " some embodiments ", " example ", " specifically show The description of example " or " some examples " etc. means specific features, structure, material or spy described in conjunction with this embodiment or example Point is included at least one embodiment or example of the invention.In the present specification, schematic expression of the above terms are not Centainly refer to identical embodiment or example.Moreover, particular features, structures, materials, or characteristics described can be any One or more embodiment or examples in can be combined in any suitable manner.
Although an embodiment of the present invention has been shown and described, it will be understood by those skilled in the art that: not A variety of change, modification, replacement and modification can be carried out to these embodiments in the case where being detached from the principle of the present invention and objective, this The range of invention is defined by the claims and their equivalents.

Claims (18)

1. a kind of compound, which is characterized in that for compound shown in formula (I) compound represented or formula (I) stereoisomer, Tautomer, nitrogen oxides, hydrate, solvate, metabolite, pharmaceutically acceptable salt or prodrug:
Each R1、R3、R5、R6、R10It is each independently hydrogen, amino, itrile group ,-ORa、C1-6Alkoxy, halogen, C1-6Alkyl, C3-6Ring Alkyl, wherein each C1-6Alkoxy, C1-6Alkyl, C3-6Naphthenic base is independently unsubstituted or independently by 1,2,3,4 or 5 A-OH ,-NH2、-NO2,-CN, halogen, C1-6Alkyl, C1-6Alkoxy or C1-6Alkylamino replaces；
R2It independently is hydrogen, hydroxyl, amino, itrile group ,-C (=O)-Rb,-C (=O)-ORc,-C (=O)-NRc1Rc2、C2-6Alkynyl, C2-6Alkenyl, C1-6Alkoxy, C1-6Alkylamino, halogen, C1-6Alkyl, C3-6Naphthenic base, C6-10Aryl, benzyl, 3-9 atom group At heterocycle, 5-10 former molecular heteroaryl, Rd- CH=N-ORc, wherein each C2-6Alkynyl, C2-6Alkenyl, C1-6 Alkoxy, C1-6Alkyl, C3-6Naphthenic base, C6-10Aryl, benzyl, 3-9 former molecular heterocycle or 5-10 atom composition Heteroaryl it is independently unsubstituted or independently by 1,2,3,4 or 5 C1-6Alkyl, C1-6Alkoxy, nitro, amino, hydroxyl, Itrile group or halogen replace；
Each R4、R7、R9、R11It is each independently hydrogen, hydroxyl, amino, itrile group, nitro ,-C (=O)-Rb,-C (=O)-ORc、-C (=O)-NRc1Rc2、C2-6Alkynyl, C2-6Alkenyl, C1-6Alkoxy, halogen, C1-6Alkyl, C3-6Naphthenic base, C6-10Aryl, benzyl, 3- The molecular heterocycle of 9 originals, 5-10 former molecular heteroaryl；Wherein, each C2-6Alkynyl, C2-6Alkenyl, C1-6Alcoxyl Base, C1-6Alkyl, C3-6Naphthenic base, C6-10The former molecular heterocycle of aryl, benzyl or 3-9 or 5-10 original are molecular miscellaneous Aryl is independently unsubstituted or independently by 1,2,3,4 or 5 C1-6Alkyl, C1-6Alkoxy, nitro, amino, itrile group or halogen Element replaces；
R8It independently is hydrogen ,-ORe, amino, itrile group, C1-6Alkoxy, C1-6Alkylamino, halogen, C1-6Alkyl, C3-6Naphthenic base, C2-6 Alkynyl, C2-6Alkenyl；
RaIt independently is hydrogen, C1-6Alkyl, C2-6Alkynyl, C2-6Alkenyl or-(C=O) C1-6Alkyl；
RbIt independently is H ,-OH ,-NH2、C1-6Alkyl, C1-6Alkoxy or C3-7Naphthenic base；
Each Rc、Rc1、Rc2、RdIt is separately H or C1-6Alkyl；
ReIt independently is hydrogen, C1-6Alkyl ,-C1-6Alkyl-NH-C (=O)-C1-6Alkyl, C1-6Halogenated alkyl,
-C1-6Alkyl-(5-6 unit's heteroaryl)-NH-C (=O)-C1-6Alkyl-(5-10 circle heterocyclic ring base)-；
Or R1With R2With together with the atom that they are respectively connected with or R2With R3With together with the atom that they are respectively connected with or Person R3With R4With together with the atom that they are respectively connected with or R4With R5With together with the atom that they are respectively connected with or R6With R7With together with the atom that they are respectively connected with or R7With R8With together with the atom that they are respectively connected with or R8With R9With with The atom that they are respectively connected with is together or R9With R10With together with the atom that they are respectively connected with or R10With R11With with they The atom being respectively connected with is together or R11With R1With together with the atom that they are respectively connected with, 4-8 circle heterocyclic ring base or C are formed4-8Ring Alkyl, wherein the 4-8 circle heterocyclic ring base or C4-8Naphthenic base is unsubstituted or optionally by 1,2,3,4 or 5 oxo, C1-6Alkane Base, C2-6Alkenyl, hydroxyl or halogen replace；
Or R5With R6With together with the atom that they are respectively connected with or R1With R6With together with the atom that they are respectively connected with or Person R5With R10With together with the atom that they are respectively connected with or R1With R10With together with the atom that they are respectively connected with, 6- is formed 8 circle heterocyclic ring bases or C6-8Naphthenic base, wherein the 6-8 circle heterocyclic ring base or C6-8Naphthenic base is unsubstituted or optionally by 1,2,3,4 Or 5 oxos, C1-6Alkyl, halogen or hydroxyl replace；
X independently is key, C1-6Alkyl, C1-6Alkoxy, amino, C1-6Alkylamino, C2-6Alkynyl, C2-6Alkenyl, Rf- C (=O)-Rg；
Each Rf、RgIt is each independently hydrogen, C1-6Alkyl, C1-6Halogenated alkyl, C1-6Hydroxy alkyl, C1-6Aminoalkyl.
2. compound according to claim 1, which is characterized in that
Each R1、R3、R5、R6、R10It is each independently hydrogen, amino, itrile group ,-ORa、C1-3Alkoxy, halogen, C1-3Alkyl, C3-6Ring Alkyl, wherein each C1-3Alkoxy, C1-3Alkyl, C3-6Naphthenic base is independently unsubstituted or independently by 1,2,3,4 or 5 A-OH ,-NH2、-NO2,-CN, halogen, C1-3Alkyl, C1-3Alkoxy or C1-3Alkylamino replaces；
R2It independently is hydrogen, hydroxyl, amino, itrile group ,-C (=O)-Rb,-C (=O)-ORc,-C (=O)-NRc1Rc2、C2-4Alkynyl, C2-4Alkenyl, C1-3Alkoxy, halogen, C1-3Alkyl, C3-6Naphthenic base, phenyl, benzyl, 5-6 former molecular heterocycle, 5-6 The molecular heteroaryl of a original, Rd- CH=N-ORc, wherein each C2-4Alkynyl, C2-4Alkenyl, C1-3Alkoxy, C1-3Alkyl, C3-6Naphthenic base, phenyl, benzyl, 5-6 former molecular heterocycle, 5-6 former molecular heteroaryl are independently unsubstituted Or independently by 1,2,3,4 or 5 C1-3Alkyl, C1-3Alkoxy, C1-3Alkylamino, nitro, amino, itrile group or halogen replace；
Each R4、R7、R9、R11It is each independently hydrogen, hydroxyl, amino, itrile group, nitro ,-C (=O)-Rb,-C (=O)-ORc、-C (=O)-NRc1Rc2、C2-4Alkynyl, C2-4Alkenyl, C1-3Alkoxy, halogen, C1-3Alkyl, C3-6Naphthenic base, phenyl, benzyl, 5-6 Former molecular heterocycle, 5-6 former molecular heteroaryl；Wherein, each C2-4Alkynyl, C2-4Alkenyl, C1-3Alkoxy, C1-3Alkyl, C3-6Naphthenic base, phenyl, benzyl, 5-6 former molecular heterocycle, 5-6 former molecular heteroaryl are independently It is unsubstituted or independently by 1,2,3,4 or 5 C1-3Alkyl, C1-3Alkoxy, nitro, amino, itrile group or halogen replace；
R8It independently is hydrogen ,-ORe, amino, itrile group, C1-3Alkoxy, C1-3Alkylamino, halogen, C1-3Alkyl, C3-6Naphthenic base, C2-4 Alkynyl, C2-4Alkenyl；
RaIt independently is hydrogen, C1-3Alkyl, C2-4Alkynyl, C2-4Alkenyl or-(C=O) C1-3Alkyl；
RbIt independently is H ,-OH ,-NH2、C1-3Alkyl or C3-6Naphthenic base；
Each Rc、Rc1、Rc2、RdIt is separately H or C1-3Alkyl；
ReIt independently is hydrogen, C1-3Alkyl ,-C1-3Alkyl-NH-C (=O)-C1-3Alkyl, C1-3Halogenated alkyl,
Or R1With R2With together with the atom that they are respectively connected with or R2With R3With together with the atom that they are respectively connected with or Person R3With R4With together with the atom that they are respectively connected with or R4With R5With together with the atom that they are respectively connected with or R6With R7With together with the atom that they are respectively connected with or R7With R8With together with the atom that they are respectively connected with or R8With R9With with The atom that they are respectively connected with is together or R9With R10With together with the atom that they are respectively connected with or R10With R11With with they The atom being respectively connected with is together or R11With R1With together with the atom that they are respectively connected with, 5-6 circle heterocyclic ring base or C are formed5-6Ring Alkyl, wherein the 5-6 circle heterocyclic ring base or C5-6Naphthenic base is unsubstituted or optionally by 1,2,3,4 or 5 oxo, C1-3Alkane Base, C2-4Alkenyl, hydroxyl or halogen replace；
Or R5With R6With together with the atom that they are respectively connected with or R1With R6With together with the atom that they are respectively connected with or Person R5With R10With together with the atom that they are respectively connected with or R1With R10With together with the atom that they are respectively connected with, 6- is formed 7 circle heterocyclic ring bases or C6-7Naphthenic base, wherein the 6-7 circle heterocyclic ring base or C6-7Naphthenic base is unsubstituted or optionally by 1,2,3,4 Or 5 oxos, C1-3Alkyl, halogen or hydroxyl replace；
X independently is key, C1-3Alkyl, C1-3Alkoxy, amino, C1-3Alkylamino, C2-4Alkynyl, C2-4Alkenyl, Rf- C (=O)-Rg；
Each Rf、RgIt is each independently hydrogen, C1-3Alkyl, C1-3Halogenated alkyl, C1-3Hydroxy alkyl.
3. compound according to claim 1, which is characterized in that it is formula (II) or (IIa) compound represented or formula (II) Or stereoisomer, tautomer, hydrate, solvate, prodrug, nitrogen oxides or the pharmacy of compound shown in (IIa) Upper acceptable salt,
4. compound according to claim 1, which is characterized in that it is formula (III) or (IIIa) compound represented or formula (III) or the stereoisomer of compound shown in (IIIa), tautomer, hydrate, solvate, prodrug, nitrogen oxides Or pharmaceutically acceptable salt,
5. compound according to claim 1, which is characterized in that it is change shown in formula (IV), (IVa), (IVb) or (IVc) Close stereoisomer, tautomer, hydrate, the solvent of compound shown in object or formula (IV), (IVa), (IVb) or (IVc) Compound, prodrug, nitrogen oxides or pharmaceutically acceptable salt,
Each R12、R13、R14、R15It is each independently hydrogen, C1-6Alkyl；
Optionally, each R12、R13、R14、R15It is each independently hydrogen, methyl, ethyl, propyl.
6. compound according to claim 1, which is characterized in that its for formula (V) or (Va) compound represented or formula (V) or (Va) stereoisomer of compound shown in, tautomer, hydrate, solvate, prodrug, nitrogen oxides pharmaceutically may be used The salt of receiving,
Each R12、R13、R14、R15It is each independently hydrogen, C1-6Alkyl；
Y is-N- or-O-；
Optionally, each R12、R13、R14、R15It is each independently hydrogen, methyl, ethyl, propyl.
7. compound according to claim 1, which is characterized in that it is shown in formula (VI) or (VIa) or (VIb) or (VIc) The stereoisomer of compound shown in compound or formula (VI) or (VIa) or (VIb) or (VIc), tautomer, hydrate, Solvate, prodrug, nitrogen oxides or pharmaceutically acceptable salt,
RwIt independently is C2-4Alkynyl, C2-4Alkenyl or C1-3Alkyl, wherein each C2-4Alkynyl, C2-4Alkenyl or C1-3Alkyl is independently not It is substituted or by 1,2,3,4 C1-3Alkyl, halogen, nitro ,-CN, OH replace；
Each R12、R13、R14、R15、R16、R17、R18、R19It is each independently hydrogen, C1-6Alkyl；
Y is-N- or-O-；
Optionally, each R12、R13、R14、R15、R16、R17、R18、R19It is each independently hydrogen, methyl, ethyl, propyl；
RwIt independently is vinyl.
8. compound according to claim 1, which is characterized in that it is formula (VII) compound represented or formula (VII) shownization Stereoisomer, tautomer, hydrate, solvate, prodrug, nitrogen oxides or the pharmaceutically acceptable salt of object are closed,
Each R12、R13、R14、R15、R16、R17、R18、R19It is each independently hydrogen, C1-6Alkyl；
Y is-N- or-O-；
Optionally, each R12、R13、R14、R15、R16、R17、R18、R19It is each independently hydrogen, methyl, ethyl, propyl.
9. compound according to claim 1, which is characterized in that its for formula (VIII) or (VIII-a) or (VIII-b) or (VIII-c) solid of compound shown in compound represented or formula (VIII) or (VIII-a) or (VIII-b) or (VIII-c) Isomers, tautomer, hydrate, solvate, prodrug, nitrogen oxides or pharmaceutically acceptable salt,
Each R12、R13、R14、R15It is each independently hydrogen, C1-6Alkyl；
RwIt independently is C2-4Alkynyl, C2-4Alkenyl or C1-3Alkyl, wherein each C2-4Alkynyl, C2-4Alkenyl or C1-3Alkyl is independently not It is substituted or by 1,2,3,4 C1-3Alkyl, halogen, nitro ,-CN, OH replace；
R16It independently is hydrogen, C1-6Alkyl；
Optionally, each R12、R13、R14、R15It is each independently hydrogen, methyl, ethyl, propyl；
Preferably, RwFor acrylic, R16For methyl, ethyl, propyl.
10. compound according to claim 1, which is characterized in that it is formula (X) or formula (X-a) or formula (X-b) or formula (X-c) Or formula (X-d) or formula (X-e) compound represented or formula (X) or formula (X-a) or formula (X-b) or formula (X-c) or formula (X-d) or formula (X-e) stereoisomer of compound shown in, tautomer, hydrate, solvate, prodrug, nitrogen oxides or pharmaceutically Acceptable salt,
Each R20、R21It is each independently hydrogen, C1-6Alkyl, C1-6Alkoxy, C3-6Naphthenic base, halogen；
Each Rb1、Rb2It is each independently H ,-OH ,-NH2、C1-6Alkoxy, C1-6Alkyl or C3-7Naphthenic base；
Each R12、R13、R14、R15It is each independently hydrogen, C1-6Alkyl；
Preferably, each R20、R21It is each independently hydrogen, methyl, ethyl, propyl, methoxyl group, ethyoxyl, n-propyl, isopropyl oxygen Base, hexamethylene, halogen；
Each Rb1、Rb2It is each independently H ,-OH ,-NH2、C1-3Alkoxy, C1-3Alkyl or C3-6Naphthenic base；
Each R12、R13、R14、R15It is each independently hydrogen, hydrogen, methyl, ethyl, propyl；
Or R20With R21With together with the atom that they are respectively connected with, 5-6 circle heterocyclic ring base or C are formed5-6Naphthenic base, wherein the 5- 6 circle heterocyclic ring bases or C5-6Naphthenic base is unsubstituted or optionally by 1,2,3,4 or 5 oxo, C1-3Alkyl, C2-4Alkenyl, hydroxyl or Halogen replaces；
Preferably, R20With R21With together with the atom that they are respectively connected with, hexamethylene is formed.
11. compound according to claim 1, which is characterized in that X is amino, C1-3Alkyl, C1-3Alkoxy, C1-6Alkylamino, Rf- C (=O)-Rg；
Preferably, X is carbon atom.
12. compound according to claim 1, which is characterized in that R11It independently is hydrogen, halogen, C1-3Alkyl, C1-3Alkoxy ,- C (=O)-Rb,-C (=O)-ORc, heterocycle that phenyl, benzyl, 5-6 atom are formed, 5-6 atom formation heteroaryl；Its In, each C1-3Alkyl, C1-3Alkoxy, phenyl, benzyl or the heterocycle of 5-6 atom formation, 5-6 atom form miscellaneous Aryl is separately unsubstituted or independently by 1,2,3,4 or 5 C1-3Alkyl, C1-3Alkoxy, nitro, amino, itrile group Or halogen replaces；
Preferably, R11For hydrogen.
13. compound according to claim 1, which is characterized in that R2It independently is hydrogen, hydroxyl, amino, itrile group ,-C (=O)- Rb,-C (=O)-ORc、C2-4Alkynyl, C2-4Alkenyl, C1-3Alkoxy, halogen, C1-3Alkyl, C5-6Naphthenic base, phenyl, benzyl, 5-6 Heterocycle, the R of a atom formationd- CH=N-ORc；Wherein, each C2-4Alkynyl, C2-4Alkenyl, C1-3Alkoxy, C1-3Alkyl, C5-6The heterocycle that naphthenic base, phenyl, benzyl or 5-6 atom are formed is independently unsubstituted or independently by 1,2,3,4 or 5 A C1-3Alkyl, C1-3Alkoxy, nitro, amino, itrile group or halogen replace；
Each Rc、RdIt is separately H or C1-3Alkyl；
Each RbIt independently is H ,-OH ,-NH2、C1-3Alkyl, C1-3Alkoxy or C3-6Naphthenic base；
Preferably, R2For hydrogen, chlorine, bromine,Cyano.
14. compound according to claim 1, which is characterized in that
Each R1、R3、R5、R6、R8、R10Be each independently is hydroxyl, hydrogen, methyl, methoxyl group, isopropoxy, butoxy, acetyl oxygen Base, propenyloxy group, 3- chloropropanol oxygen radical, 3- acetamide propoxyl group；
Each R4Stand alone as hydrogen, methyl, cyano, acetoxyl group, trifluoromethyl, nitro, halogen；
Each R8It independently is hydroxyl, methoxyl group, acetoxyl group, chloroethoxy, propargyl alcoholate；
Each R7It independently is hydrogen, methyl, cyano, carbonyl, acetyl group, trifluoromethyl, halogen；
Each R11It independently is hydrogen, methyl, phenyl, 4- fluorophenyl；
Each R2、R9It is each independently hydrogen, methyl, ethyl, propyl, hexyl, cyclopropyl, isobutyl group, 2- methyl-propyl；
Each R12、R13、R14、R15、R16、R17、R18、R19Being each independently is hydrogen, methyl, ethyl, propyl；Or R9And R10It is connected as Benzo isozole ring, wherein benzo isozole ring is independently by 1,2,3,4 or 5 H, C1-3Alkyl；
Or R1And R2, R8And R9Close simultaneously is chromanone ring, wherein chromanone ring is independently by 1,2,3,4 or 5 H, C1-3Alkyl；
Or R2And R3, R9And R10Close simultaneously is chromanone ring, wherein chromanone ring is independently by 1,2,3,4 or 5 H, C1-3Alkane Base；
Or R2And R3It is connected as chromanone ring or 2,3- dihydro-quinolinone ring, wherein chromanone ring or 2,3- dihydro-quinolinone ring are only On the spot by 1,2,3,4 or 5 H, C1-3Alkyl；
Or R8And R9It is connected as chromanone ring；
Or R1And R2It is connected as chroman ring or chromanone ring or 2,3- dihydro-quinolinone ring, wherein chroman ring or chromanone ring or 2, 3- dihydro-quinolinone ring is independently by 1,2,3,4 or 5 H, C1-3Alkyl；
Or R9And R10It is connected as chroman ring or chromanone ring；
Or R1And R2It is connected as benzo five-membered lactonic ring, wherein benzo five-membered lactonic ring is independently by 1,2,3,4 or 5 H, C1-3 Alkyl, C2-4Alkenyl, C2-4Alkynyl；
Or R5And R6It is connected as seven yuan of ether rings；
Or R8And R9Closing is chromanone ring, wherein chromanone ring is independently by 1,2,3,4 or 5 H, C1-3Alkyl；
Or R9And R10Closing is chromanone ring, wherein chromanone ring is independently by 1,2,3,4 or 5 H, C1-3Alkyl；
Or R2And R3It is connected as coumarin ring, wherein coumarin ring is independently by 1,2,3,4 or 5 H, C1-3Alkyl, C5-6Cycloalkanes Base, halogen replace；
Or R8And R9Closing is chromanone ring, wherein chromanone ring is independently by 1,2,3,4 or 5 H, C1-3Alkyl；
Or R9And R10Closing is chromanone ring, wherein chromanone ring is independently by 1,2,3,4 or 5 H, C1-3Alkyl.
15. compound according to claim 1, which is characterized in that its have it is one of following shown in structure or its alloisomerism Body, tautomer, nitrogen oxides, hydrate, solvate, metabolite, pharmaceutically acceptable salt or prodrug,
16. a kind of pharmaceutical composition, which is characterized in that described pharmaceutical composition includes claim 1-15 described in any itemization Close object.
17. pharmaceutical composition according to claim 16, which is characterized in that further include pharmaceutically acceptable auxiliary Material, excipient, carrier, solvent or their combination；
Optionally, described pharmaceutical composition further includes other therapeutic agents, and the other therapeutic agents are selected from antituberculotic, resist HIV drug, the drug for treating diabetes；
Optionally, the antituberculotic is isoniazid, rifampin, ethambutol or pyrazinamide；
Optionally, the inverase is Sustiva or nevirapine.
18. pharmaceutical composition described in the described in any item compounds of claim 1-15 or claim 16 or 17 is preparing medicine Purposes in object, the drug is for preventing and/or treating children's tuberculosis, pulmonary tuberculosis, intestinal tuberculosis, scrofula, bone tuberculosis, kidney Tuberculosis, tubercular peritonitis, tubercular meningitis, drug susceptibility tuberculosis, multidrug resistance tuberculosis, extensive drug resistance knot Core disease, latent tuberculosis disease, the tuberculosis of HIV concurrent infection or disease relevant to mycobacterium tuberculosis infection.
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