CN109293493B - Novel benzhydryl compounds with mycobacterium tuberculosis inhibiting activity - Google Patents

Novel benzhydryl compounds with mycobacterium tuberculosis inhibiting activity Download PDF

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CN109293493B
CN109293493B CN201811268731.9A CN201811268731A CN109293493B CN 109293493 B CN109293493 B CN 109293493B CN 201811268731 A CN201811268731 A CN 201811268731A CN 109293493 B CN109293493 B CN 109293493B
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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 novel benzhydryl derivatives having activity of inhibiting mycobacterium tuberculosis and a method for preparing the same, and more particularly, to novel benzhydryl derivatives having activity of inhibiting replicating and non-replicating mycobacterium tuberculosis and a method for preparing the same. In particular, the invention relates to a compound shown as a formula (I) or all possible isomers, prodrugs, pharmaceutically acceptable salts, solvates or water thereofThe compound, wherein the variables are as described in the specification. Also relates to a preparation method of the compound, a pharmaceutical composition containing the compound and application of the compound in preparing medicaments for resisting diseases caused by mycobacterium tuberculosis infection.

Description

Novel benzhydryl compounds with mycobacterium tuberculosis inhibiting activity
Technical Field
The present invention relates to novel benzhydryl derivatives having activity of inhibiting mycobacterium tuberculosis and a process for their preparation, in particular to novel benzhydryl derivatives having activity of inhibiting replicating and non-replicating mycobacterium tuberculosis and a process for their preparation as well as the use of said compounds, either alone or in combination, for the preparation of a medicament against diseases caused by mycobacterium tuberculosis infection.
Background
Tuberculosis (TB) is one of the most serious and serious fatal infectious diseases caused by Mycobacterium Tuberculosis (Mtb) and still seriously affects the health of human beings. In 1993, the World Health Organization (WHO) announced "global tuberculosis emergency", and determined that 24 days in 3 months per year was "worldwide tuberculosis prevention day". In 1998, the world health organization reiterated that the suppression of TB was not slow enough. Currently, more than 1/4 of the world's population has become infected with Mtb, with at least 200 million people dying from TB each year. Drug resistance and latency in tuberculosis are significant challenges encountered in the treatment of tuberculosis. Statistics show that each year, there are 60 million new cases of multi-drug resistant tuberculosis (MDR-TB), and the treatment of people infected with widely drug resistant tuberculosis (XDR-TB) is more complicated. Latent tuberculosis (late TB) is considered to be another major cause of the long treatment period at present. Tubercle bacillus has two kinds of replication (replication Mtb) and non-replication (non-replication Mtb), and the latter is considered as the main cause of TB recurrence and long treatment period up to 6-9 months. The tuberculosis treatment has the characteristics of long period and multiple drug types, and the combined use of the anti-tuberculosis drugs and other drugs (such as drugs for treating AIDS and other chronic syndromes) also needs special attention.
To date, the primary strategy for treating tuberculosis remains chemotherapy. First-line anti-TB drugs used clinically include isoniazid, rifampin, pyrazinamide, and ethambutol. The clinical treatment scheme for the drug sensitive TB is to orally take the four drugs for 2 months every day and then orally take the isoniazid and the rifampicin for 4 months every day. MDR-TB is drug resistant to isoniazid and rifampicin, and after infection, the MDR-TB needs to be combined with second-line drugs, so that the treatment period is prolonged to 2 years, and the cure rate is about 50-70%. XDR-TB refers to resistance to not only isoniazid and rifampin in the first line of drugs, but also to at least one fluoroquinolone drug and at least one injectable anti-TB drug in the second line of drugs. The mortality rate for treating XDR-TB is very high due to drug resistance and immune tolerance among patients. The treatment of people with combined TB and AIDs infections is more challenging due to the low immunity of HIV patients, which greatly reduces the efficacy of the drugs. Currently, about 50% of AIDs die from co-infection with Mtb.
The Mycobacterium tuberculosis is aerobic bacteria, and has growth temperature of 37 deg.C and optimal growth pH value of 6.8-7.2. When the pH value in the bacteria (intrabacterial pH, pH)IB) Below 5.5, the replication of mycobacterium tuberculosis is severely inhibited. However, M.tuberculosis is able to withstand the acidic environment within host macrophages, maintaining its pHIBSteady state, entering a non-replicated state and persisting. Once an adaptive environment is obtained, such as immune compromised, the retained Mycobacterium tuberculosis develops into replicating Mycobacterium tuberculosis.
After the body is infected with mycobacterium tuberculosis, the mycobacterium tuberculosis is phagocytized by a phagosome (phagosome). Whereas mycobacterium tuberculosis can generally survive in a relatively mild pH (6.2) environment by inhibiting phagosome maturation and fusion of phagosomes with lysosomes. However, when the specific immune system is activated, the T-cells release gamma-interferon (INF-gamma), which in turn promotes the maturation of phagosome and further promotes the fusion of phagosome and lysosome into phagolysosome, which is on the membrane and H+The V-ATPase protein related to active transport reduces the pH value in the membrane to 4.5-5.0, greatly enhances the acidic environment in the phagolysosome, and causes H+There is a strong tendency to diffuse into Mtb, which in turn lowers the pH in the body of Mtb and inhibits the replication activity of Mtb. In addition, it is also explained that large amounts of H + may support and coordinate other antimicrobial mechanisms within macrophages, e.g., H + may further activate Reactive Nitrogen Intermediates (RNI) and Reactive Oxygen Intermediates (ROI), free fatty acids, and,Ubiquitin-derived peptides, and lysosomal hydrolase activity, among others.
Mtb, in order to combat and withstand this acidic environment, forms a protective system to maintain pH by itselfIBAnd then becomes latent. It is presently believed that the pH involved in MtbIBThe major homeostatic effects include the outer membrane protein (OmpATb), the magnesium ion transporter (MgtC), and the serine protease encoded by the Rv3671c gene.
Agrimophol is a phloroglucinol compound with obvious tapeworm expelling activity separated from the root bud of the common traditional Chinese medicine agrimony by Chinese scientists, the whole herb of the compound is used for stopping bleeding and diminishing inflammation, and the root and stem of the compound can be used for treating dysentery; there is no report on the inhibitory activity of agrimophol on M.tuberculosis at present.
Figure BDA0001845508230000011
There is still a need for new compounds that are effective in the treatment of tuberculosis, in particular for the treatment of latent tuberculosis and significantly shorten the treatment period for tuberculosis.
Disclosure of Invention
The invention relates to a novel benzhydryl compound and application thereof in preparing medicaments for treating mycobacterium tuberculosis infection related diseases, in particular to application in preparing medicaments for treating replicating and non-replicating mycobacterium tuberculosis infection and related diseases thereof, and particularly relates to a novel benzhydryl compound and a pharmaceutically acceptable composition thereof.
In a first aspect of the invention, the invention features a compound. According to an embodiment of the invention is a compound of formula (I) or a stereoisomer, a tautomer, a nitrogen oxide, a hydrate, a solvate, a metabolite, a pharmaceutically acceptable salt, or a prodrug of a compound of formula (I):
Figure BDA0001845508230000021
each R1、R3、R5、R6、R10Each independently hydrogen, amino, nitrile, -ORa、C1-6Alkoxy, halogen, C1-6Alkyl radical, C3-6Cycloalkyl, wherein each of said C1-6Alkoxy radical, C1-6Alkyl radical, C3-6Cycloalkyl is independently unsubstituted or independently substituted with 1,2,3, 4 or 5-OH, -NH2、-NO2-CN, halogen, C1-6Alkyl radical, C1-6Alkoxy or C1-6Alkyl amino substitution;
R2independently hydrogen, hydroxy, amino, nitrile, -C (═ O) -Rb、-C(＝O)-ORc、-C(＝O)-NRc1Rc2、C2-6Alkynyl, C2-6Alkenyl radical, C1-6Alkoxy radical, C1-6Alkylamino, halogen, C1-6Alkyl radical, C3-6Cycloalkyl radical, C6-10Aryl, benzyl, heterocyclic group consisting of 3-9 atoms, heteroaryl group consisting of 5-10 atoms, Rd-CH＝N-ORcWherein each of C2-6Alkynyl, C2-6Alkenyl radical, C1-6Alkoxy radical, C1-6Alkyl radical, C3-6Cycloalkyl radical, C6-10Aryl, benzyl, heterocyclyl of 3 to 9 atoms or heteroaryl of 5 to 10 atoms independently unsubstituted or independently substituted by 1,2,3, 4 or 5C1-6Alkyl radical, C1-6Alkoxy, nitro, amino, hydroxyl, nitrile or halogen substitution;
each R4、R7、R9、R11Each independently is hydrogen, hydroxy, amino, nitrile, nitro, -C (═ O) -Rb、-C(＝O)-ORc、-C(＝O)-NRc1Rc2、C2-6Alkynyl, C2-6Alkenyl radical, C1-6Alkoxy, halogen, C1-6Alkyl radical, C3-6Cycloalkyl radical, C6-10Aryl, benzyl, heterocyclic group consisting of 3-9 atoms and heteroaryl consisting of 5-10 atoms; wherein each C is2-6Alkynyl, C2-6Alkenyl radical, C1-6Alkoxy radical, C1-6Alkyl radical, C3-6Cycloalkyl radical, C6-10Aryl, benzyl, heterocyclyl of 3 to 9 atoms, heteroaryl of 5 to 10 atoms independently unsubstituted or independently substituted by 1,2,3, 4 or 5C1-6Alkyl radical, C1-6Alkoxy, nitro, amino, nitrile or halogen substitution;
R8independently hydrogen, -OReAmino, nitrile, C1-6Alkoxy radical, C1-6Alkylamino, halogen, C1-6Alkyl radical, C3-6Cycloalkyl radical, C2-6Alkynyl, C2-6An alkenyl group;
Raindependently of one another is hydrogen, C1-6Alkyl radical, C2-6Alkynyl, C2-6Alkenyl or- (C ═ O) C1-6An alkyl group;
Rbindependently is H, -OH, -NH2、C1-6Alkyl radical, C1-6Alkoxy or C3-7A cycloalkyl group;
each Rc、Rc1、Rc2、RdEach independently is H or C1-6An alkyl group;
Reindependently of one another is hydrogen, C1-6Alkyl, -C1-6alkyl-NH-C (═ O) -C1-6Alkyl radical, C1-6A halogenated alkyl group,
-C1-6Alkyl- (5-6 membered heteroaryl) -NH-C (═ O) -C1-6Alkyl- (5-10 membered heterocyclyl) -;
or R1And R2Together with the atom to which they are respectively attached or R2And R3Together with the atom to which they are respectively attached or R3And R4Together with the atom to which they are respectively attached or R4And R5Together with the atom to which they are respectively attached or R6And R7Together with the atom to which they are respectively attached or R7And R8Together with the atom to which they are respectively attached or R8And R9Together with the atom to which they are respectively attached or R9And R10Together with the atom to which they are respectively attached or R10And R11Together with the atom to which they are respectively attached or R11And R1And together with the atom to which they are attached, respectively, form a 4-to 8-membered heterocyclic group or C4-8Cycloalkyl, wherein said 4-8 membered heterocyclyl or C4-8Cycloalkyl unsubstituted or optionally substituted by 1,2,3, 4 or 5 oxo, C1-6Alkyl radical, C2-6Alkenyl, hydroxy or halogen;
or R5And R6Together with the atom to which they are respectively attached or R1And R6Together with the atom to which they are respectively attached or R5And R10Together with the atom to which they are respectively attached or R1And R10And together with the atom to which they are attached, respectively, form a 6-to 8-membered heterocyclic group or C6-8Cycloalkyl, wherein said 6-8 membered heterocyclyl or C6-8Cycloalkyl unsubstituted or optionally substituted by 1,2,3, 4 or 5 oxo, C1-6Alkyl, halogen or hydroxy substitution;
x is independently a bond, C1-6Alkyl radical, C1-6Alkoxy, amino, C1-6Alkylamino radical, C2-6Alkynyl, C2-6Alkenyl radical, Rf-C(＝O)-Rg；
Each Rf、RgEach independently is hydrogen, C1-6Alkyl radical, C1-6Haloalkyl, C1-6Hydroxyalkyl radical, C1-6An aminoalkyl group.
According to an embodiment of the present invention, the above compound may further include at least one of the following additional technical features:
according to an embodiment of the invention, each R1、R3、R5、R6、R10Each independently hydrogen, amino, nitrile, -ORa、C1-3Alkoxy, halogen, C1-3Alkyl radical, C3-6Cycloalkyl, wherein each of said C1-3Alkoxy radical, C1-3Alkyl radical, C3-6Cycloalkyl is independently unsubstituted or independently substituted with 1,2,3, 4 or 5-OH, -NH2、-NO2-CN, halogen, C1-3Alkyl radical, C1-3Alkoxy or C1-3Alkyl amino substitution;
R2independently hydrogen, hydroxy, amino, nitrile, -C (═ O) -Rb、-C(＝O)-ORc、-C(＝O)-NRc1Rc2、C2-4Alkynyl, C2-4Alkenyl radical, C1-3Alkoxy, halogen, C1-3Alkyl radical, C3-6Cycloalkyl, phenyl, benzyl, heterocyclyl of 5-6 atoms, heteroaryl of 5-6 atoms, Rd-CH＝N-ORcWherein each of C2-4Alkynyl, C2-4Alkenyl radical, C1-3Alkoxy radical, C1-3Alkyl radical, C3-6Cycloalkyl, phenyl, benzyl 5-6 atom heterocyclyl or 5-6 atom heteroaryl independently unsubstituted or independently substituted with 1,2,3, 4 or 5C1-3Alkyl radical, C1-3Alkoxy radical, C1-3Alkylamino, nitro, amino, nitrile or halogen;
each R4、R7、R9、R11Each independently is hydrogen, hydroxy, amino, nitrile, nitro, -C (═ O) -Rb、-C(＝O)-ORc、-C(＝O)-NRc1Rc2、C2-4Alkynyl, C2-4Alkenyl radical, C1-3Alkoxy, halogen, C1-3Alkyl radical, C3-6Cycloalkyl, phenyl, benzyl, heterocyclic group consisting of 5-6 atoms and heteroaryl group consisting of 5-6 atoms; wherein each C is2-4Alkynyl, C2-4Alkenyl radical, C1-3Alkoxy radical, C1-3Alkyl radical, C3-6Cycloalkyl, phenyl, benzyl 5-6 atom heterocyclyl or 5-6 atom heteroaryl independently unsubstituted or independently substituted with 1,2,3, 4 or 5C1-3Alkyl radical, C1-3Alkoxy, nitro, amino, nitrile or halogen substitution;
R8independently hydrogen, -OReAmino, nitrile group,C1-3Alkoxy radical, C1-3Alkylamino, halogen, C1-3Alkyl radical, C3-6Cycloalkyl radical, C2-4Alkynyl, C2-4An alkenyl group;
Raindependently of one another is hydrogen, C1-3Alkyl radical, C2-4Alkynyl, C2-4Alkenyl or- (C ═ O) C1-3An alkyl group;
Rbindependently is H, -OH, -NH2、C1-3Alkyl radical, C1-3Alkoxy or C3-6A cycloalkyl group;
each Rc、Rc1、Rc2、RdEach independently is H or C1-3An alkyl group;
Reindependently of one another is hydrogen, C1-3Alkyl, -C1-3alkyl-NH-C (═ O) -C1-3Alkyl radical, C1-3A halogenated alkyl group,
Figure BDA0001845508230000031
Or R1And R2Together with the atom to which they are respectively attached or R2And R3Together with the atom to which they are respectively attached or R3And R4Together with the atom to which they are respectively attached or R4And R5Together with the atom to which they are respectively attached or R6And R7Together with the atom to which they are respectively attached or R7And R8Together with the atom to which they are respectively attached or R8And R9Together with the atom to which they are respectively attached or R9And R10Together with the atom to which they are respectively attached or R10And R11Together with the atom to which they are respectively attached or R11And R1And together with the atom to which they are attached, respectively, form a 5-6 membered heterocyclic group or C5-6Cycloalkyl, wherein said 5-6 membered heterocyclyl or C5-6Cycloalkyl unsubstituted or optionally substituted by 1,2,3, 4 or 5 oxo, C1-3Alkyl radical, C2-4Alkenyl, hydroxy or halogen;
or R5And R6Together with the atom to which they are respectively attached or R1And R6Together with the atom to which they are respectively attached or R5And R10Together with the atom to which they are respectively attached or R1And R10And together with the atom to which they are attached, respectively, form a 6-to 7-membered heterocyclic group or C6-7Cycloalkyl, wherein said 6-7 membered heterocyclyl or C6-7Cycloalkyl unsubstituted or optionally substituted by 1,2,3, 4 or 5 oxo, C1-3Alkyl, halogen or hydroxy substitution;
x is independently a bond, C1-3Alkyl radical, C1-3Alkoxy, amino, C1-3Alkylamino radical, C2-4Alkynyl, C2-4Alkenyl radical, Rf-C(＝O)-Rg；
Each Rf、RgEach independently is hydrogen, C1-3Alkyl radical, C1-3Haloalkyl, C1-3A hydroxyalkyl group.
According to an embodiment of the present invention, it is a compound represented by formula (II) or (IIa) or a stereoisomer, a tautomer, a hydrate, a solvate, a prodrug, a nitrogen oxide, or a pharmaceutically acceptable salt of the compound represented by formula (II) or (IIa),
Figure BDA0001845508230000032
according to an embodiment of the present invention, it is a compound represented by formula (III) or (IIIa) or a stereoisomer, a tautomer, a hydrate, a solvate, a prodrug, a nitrogen oxide, or a pharmaceutically acceptable salt of the compound represented by formula (III) or (IIIa),
Figure BDA0001845508230000033
according to an embodiment of the invention, it is a compound of formula (IV), (IVa), (IVb) or (IVc) or a stereoisomer, a tautomer, a hydrate, a solvate, a prodrug, a nitrogen oxide or a pharmaceutically acceptable salt of a compound of formula (IV), (IVa), (IVb) or (IVc),
Figure BDA0001845508230000034
each R12,R13,R14,R15Each independently of the other being hydrogen, C1-6An alkyl group.
According to an embodiment of the invention, each R12,R13,R14,R15Each independently hydrogen, methyl, ethyl, propyl.
According to an embodiment of the present invention, which is a compound represented by formula (V) or (Va) or a stereoisomer, a tautomer, a hydrate, a solvate, a prodrug, a nitrogen oxide, or a pharmaceutically acceptable salt of the compound represented by formula (V) or (Va),
Figure BDA0001845508230000041
each R12、R13、R14、R15Each independently of the other being hydrogen, C1-6An alkyl group; y is-N-or-O-.
According to an embodiment of the invention, each R12、R13、R14、R15Each independently hydrogen, methyl, ethyl, propyl.
According to embodiments of the invention, it is a compound of formula (VI) or (VIa) or (VIb) or (VIc) or a stereoisomer, tautomer, hydrate, solvate, prodrug, nitroxide or pharmaceutically acceptable salt of a compound of formula (VI) or (VIa) or (VIb) or (VIc),
Figure BDA0001845508230000042
Rwindependently is C2-4Alkynyl, C2-4Alkenyl or C1-3Alkyl radical, wherein each C2-4Alkynyl, C2-4Alkenyl or C1-3Alkyl is independently unsubstituted or substituted by 1,2,3, 4C1-3Alkyl, halogen, nitro, -CN, OH;
each R12、R13、R14、R15、R16、R17、R18、R19Each independently of the other being hydrogen, C1-6An alkyl group; y is-N-or-O-.
According to an embodiment of the invention, each R12、R13、R14、R15、R16、R17、R18、R19Each independently of the others is hydrogen, methyl, ethyl, propyl, RwIndependently a vinyl group.
According to an embodiment of the present invention, which is a compound represented by formula (VII) or a stereoisomer, a tautomer, a hydrate, a solvate, a prodrug, a nitrogen oxide, or a pharmaceutically acceptable salt of the compound represented by formula (VII),
Figure BDA0001845508230000043
each R12、R13、R14、R15、R16、R17、R18、R19Each independently of the other being hydrogen, C1-6An alkyl group; y is-N-or-O-.
According to an embodiment of the invention, each R12、R13、R14、R15、R16、R17、R18、R19Each independently hydrogen, methyl, ethyl, propyl.
According to an embodiment of the present invention, it is a compound represented by formula (VIII) or (VIII-a) or (VIII-b) or (VIII-c) or a stereoisomer, tautomer, hydrate, solvate, prodrug, nitrogen oxide or pharmaceutically acceptable salt of a compound represented by formula (VIII) or (VIII-a) or (VIII-b) or (VIII-c),
Figure BDA0001845508230000044
Figure BDA0001845508230000051
each R12、R13、R14、R15Each independently of the other being hydrogen, C1-6Alkyl radical
Each RwIndependently is C2-4Alkynyl, C2-4Alkenyl or C1-3Alkyl radical, wherein each C2-4Alkynyl, C2-4Alkenyl or C1-3Alkyl is independently unsubstituted or substituted by 1,2,3, 4C1-3Alkyl, halogen, nitro, -CN, OH; r16Independently of one another is hydrogen, C1-6An alkyl group.
According to an embodiment of the invention, each R12、R13、R14、R15Each independently hydrogen, methyl, ethyl, propyl.
According to an embodiment of the invention, RwIs propenyl, R16Methyl, ethyl and propyl.
According to an embodiment of the present invention, it is a stereoisomer, a tautomer, a hydrate, a solvate, a prodrug, a nitrogen oxide, or a pharmaceutically acceptable salt of the compound represented by formula (X) or formula (X-a) or formula (X-b) or formula (X-c) or formula (X-d) or formula (X-e) or the compound represented by formula (X) or formula (X-a) or formula (X-b) or formula (X-c) or formula (X-d) or formula (X-e),
Figure BDA0001845508230000052
each R20、R21Each independently is hydrogen, C1-6Alkyl radical, C1-6Alkoxy radical, C3-6Cycloalkyl, halogen;
each Rb1、Rb2Each independently of the other is H, -OH, -NH2、C1-6Alkoxy radical, C1-6Alkyl or C3-7A cycloalkyl group;
each R12、R13、R14、R15Each independently of the other being hydrogen, C1-6An alkyl group.
According to an embodiment of the invention, each R20、R21Each independently hydrogen, methyl, ethyl, propyl, methoxy, ethoxy, n-propyl, isopropoxy, cyclohexane, halogen. Each Rb1、Rb2Each independently of the other is H, -OH, -NH2、C1-3Alkoxy radical, C1-3Alkyl or C3-6A cycloalkyl group; each R12、R13、R14、R15Each independently hydrogen, methyl, ethyl, propyl.
Or R20And R21And together with the atom to which they are attached, respectively, form a 5-6 membered heterocyclic group or C5-6Cycloalkyl, wherein said 5-6 membered heterocyclyl or C5-6Cycloalkyl unsubstituted or optionally substituted by 1,2,3, 4 or 5 oxo, C1-3Alkyl radical, C2-4Alkenyl, hydroxy or halogen;
according to an embodiment of the present invention, R20And R21And together with the atoms to which they are respectively attached, form cyclohexane.
According to an embodiment of the invention, X is amino, C1-3Alkyl radical, C1-3Alkoxy radical, C1-6Alkylamino radical, Rf-C(＝O)-Rg。
According to an embodiment of the invention, X is a carbon atom.
According to an embodiment of the invention, R11Independently of one another hydrogen, halogen, C1-3Alkyl radical, C1-3Alkoxy, -C (═ O) -Rb、-C(＝O)-ORcPhenyl, benzyl, heterocyclyl of 5 to 6 atoms, heteroaryl of 5 to 6 atoms; wherein each C is1-3Alkyl radical, C1-3Alkoxy, phenyl, benzyl, heterocyclyl of 5 to 6 atoms or heteroaryl of 5 to 6 atoms are each independently unsubstituted or independently substituted by 1,2,3, 4 or 5C1-3Alkyl radical, C1-3Alkoxy, nitro, amino, nitrile or halogen.
According to an embodiment of the invention, R11Is hydrogen.
According to an embodiment of the invention, R2Independently hydrogen, hydroxy, amino, nitrile, -C (═ O) -Rb、-C(＝O)-ORc、C2-4Alkynyl, C2-4Alkenyl radical, C1-3Alkoxy, halogen, C1-3Alkyl radical, C5-6Cycloalkyl, phenyl, benzyl, heterocyclyl of 5 to 6 atoms, Rd-CH＝N-ORc(ii) a Wherein each C is2-4Alkynyl, C2-4Alkenyl radical, C1-3Alkoxy radical, C1-3Alkyl radical, C5-6Cycloalkyl, phenyl, benzyl or heterocyclyl of 5 to 6 atoms independently unsubstituted or independently substituted by 1,2,3, 4 or 5C1-3Alkyl radical, C1-3Alkoxy, nitro, amino, nitrile or halogen substitution;
each Rc、RdEach independently is H or C1-3An alkyl group;
each RbIndependently is H, -OH, -NH2、C1-3Alkyl or C3-6A cycloalkyl group.
According to an embodiment of the invention, R2Is a mixture of hydrogen, chlorine, bromine,
Figure BDA0001845508230000053
a cyano group.
According to an embodiment of the invention, each R1、R3、R5、R6、R8、R10Each independently is hydroxy, hydrogen, methyl, methoxy, isopropoxy, butoxy, acetoxy, propenyloxy, 3-chloropropyloxy, 3-acetamidopropoxy;
each R4Independently hydrogen, chlorine, bromine, methyl, fluorine, cyano, carbonyl;
each R8Independently is methoxy;
each R7Independently hydrogen, methyl, fluoro, chloro, bromo, cyano, carbonyl;
each R11Independently hydrogen, methyl, phenyl, 4-fluorophenyl;
each R2、R9Each of which isIndependently hydrogen, methyl, ethyl, propyl, hexyl, cyclopropyl, isobutyl, 2-methylpropyl;
each R12、R13、R14、R15、R16、R17、R18、R19Each independently is hydrogen, methyl, ethyl, propyl;
or R9And R10Linked as a benzisoxazole ring wherein the benzisoxazole ring is independently substituted with 1,2,3, 4 or 5H, C1-3An alkyl group;
or R1And R2，R8And R9And simultaneously closed to chromanone rings, wherein the chromanone rings are independently substituted by 1,2,3, 4 or 5H, C1-3An alkyl group;
or R2And R3，R9And R10And simultaneously closed to chromanone rings, wherein the chromanone rings are independently substituted by 1,2,3, 4 or 5H, C1-3An alkyl group;
or R2And R3Linked as a chromanone ring or a 2, 3-dihydroquinolinone ring, wherein the chromanone ring or 2, 3-dihydroquinolinone ring is independently substituted with 1,2,3, 4 or 5H, C1-3An alkyl group;
or R8And R9Linked as a chromanone ring;
or R1And R2Linked as a chroman ring or chromanone ring or 2, 3-dihydroquinolinone ring, wherein the chroman ring or chromanone ring or 2, 3-dihydroquinolinone ring is independently substituted with 1,2,3, 4 or 5H, C1-3An alkyl group;
or R9And R10Linked as chroman or chromanone rings;
or R1And R2Linked as a benzo pentalactone ring wherein the benzo pentalactone ring is independently substituted with 1,2,3, 4 or 5H, C1-3Alkyl radical, C2-4Alkenyl radical, C2-4An alkynyl group;
or R5And R6The linkage is a seven-membered ether ring;
or R8And R9Relates to chromanone rings, wherein, chromanone rings are independently substituted by 1,2,3, 4 or 5H, C1-3An alkyl group;
or R9And R10Relates to chromanone rings, wherein the chromanone ring is independently substituted with 1,2,3, 4 or 5H, C1-3An alkyl group;
or R2And R3Linked as a coumarine ring, wherein the coumarine ring is independently substituted with 1,2,3, 4 or 5H, C1-3Alkyl radical, C5-6Cycloalkyl, halo substituted;
or R8And R9Relates to chromanone rings, wherein the chromanone ring is independently substituted with 1,2,3, 4 or 5H, C1-3An alkyl group;
or R9And R10Relates to chromanone rings, wherein the chromanone ring is independently substituted with 1,2,3, 4 or 5H, C1-3An alkyl group.
According to an embodiment of the present invention, it has a structure shown in one of the following or a stereoisomer, tautomer, nitrogen oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof,
Figure BDA0001845508230000061
Figure BDA0001845508230000071
Figure BDA0001845508230000081
Figure BDA0001845508230000091
Figure BDA0001845508230000101
Figure BDA0001845508230000111
Figure BDA0001845508230000121
Figure BDA0001845508230000131
in a second aspect of the invention, a pharmaceutical composition is provided. According to an embodiment of the invention, the pharmaceutical composition comprises a compound as described above. The inventor finds that the compound has the advantages of better activity of reducing the pH value in bacteria, higher activity of inhibiting the growth of mycobacterium tuberculosis, better stability of human liver microsomes, lower cytotoxicity, higher activity of inhibiting the growth of clinically separated MDR-TB and XDR-TB and the like, and further the pharmaceutical composition containing the compound can effectively treat and prevent diseases related to the mycobacterium tuberculosis infection, particularly replicative and non-replicative mycobacterium tuberculosis infection and related diseases thereof.
According to an embodiment of the present invention, the pharmaceutical composition further comprises a pharmaceutically acceptable adjuvant, excipient, carrier, vehicle or combination thereof.
According to an embodiment of the present invention, the pharmaceutical composition further comprises an additional therapeutic agent selected from the group consisting of an anti-tubercular drug, an anti-HIV drug, a drug for treating diabetes.
According to an embodiment of the invention, the anti-tuberculosis drug is isoniazid, rifampin, ethambutol or pyrazinamide.
According to an embodiment of the invention, the anti-HIV drug is efavirenz or nevirapine.
In a third aspect, the present invention provides the use of a compound as hereinbefore described or a pharmaceutical composition as hereinbefore described in the manufacture of a medicament. The medicine is used for preventing and/or treating children tuberculosis, pulmonary tuberculosis, intestinal tuberculosis, lymphoid tuberculosis, bone tuberculosis, renal tuberculosis, tuberculous peritonitis, tuberculous meningitis, drug-sensitive tuberculosis, multidrug-resistant tuberculosis, wide drug-resistant tuberculosis, latent tuberculosis, HIV-infected tuberculosis or diseases related to tubercle bacillus infection.
In another aspect of the invention, the invention features methods for the preparation, isolation and purification of a compound of formula (I) or a stereoisomer, tautomer, nitrogen oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt or prodrug of a compound of formula (I).
The foregoing merely summarizes certain aspects of the invention and is not intended to be limiting. These and other aspects will be more fully described below.
Drawings
FIG. 1 is a graph of the results of a HepG2 cytotoxicity assay evaluation in which (A) agrimol, example compounds 122 and 128, dose curves to lower pH in BCG bacteria, with the EC of agrimol, according to an embodiment of the present invention50EC for example Compound 122 with a value of 0.9669. mu.M50EC for example 128 with a value of 0.06502 μ M50The EC for example compounds 122 and 128 compared to agrimol was 0.0618. mu.M 501 order of magnitude increase, (B) a dose curve of agrimol, example compounds 122 and 128, at different concentrations, inhibiting HepG2 cell growth; IC of agrimophol50IC value of 3.383 μ M, example Compound 12250IC of 15.69 μ M value, example Compound 12850The value was 4.375. mu.M;
FIG. 2 is a graph of the in vitro evaluation of Mtb and the clinically isolated MDR-Mtb and XDR-Mtb survival activities according to an embodiment of the present invention, wherein (A) agrimol, example compounds 122 and 128, in vitro, were evaluated for inhibition of Mtb survival activity; wherein example compound 122 was able to reduce CFU by 1.5 orders of magnitude at 0.78 μ M and 3.125 μ M by 3 orders of magnitude; agrimophol and example compound 128 were able to reduce CFU by 1 order of magnitude at 3.125 μ M; example compound 122 had a 1 order of magnitude increase in Mtb growth inhibition activity in vitro compared to agrimol, (B) agrimol, example compound 122 and128 in vitro inhibition of MDR-Mtb survival activity evaluation; MIC where example Compound 122 and Agrimophol inhibit the growth of MDR-Mtb90Value 1.56. mu.M, MIC of example Compound 12890The value was 12.5 μ M, (C) agrimol, example compound 122 and 128 evaluation of in vitro inhibition of XDR-Mtb survival activity; MIC where example Compound 122 and Agrimophol inhibit the growth of XDR-Mtb90Value 6.25. mu.M, MIC of example Compound 12890Value is>12.5μM。
Detailed Description
Detailed description of the invention
Definitions and general terms
The invention will be described in detail in the literature corresponding to the identified embodiments, and the examples are accompanied by the graphic illustrations of structural formulae and chemical formulae. The present invention is intended to cover all alternatives, modifications and equivalents, which may be included within the scope of the present invention as defined by the appended claims. Those skilled in the art will recognize many methods and materials similar or equivalent to those described herein which can be used in the practice of the present invention. The present invention is in no way limited to the description of methods and materials. There are many documents and similar materials that may be used to distinguish or contradict the present application, including, but in no way limited to, the definition of terms, their usage, the techniques described, or the scope as controlled by the present application.
The following definitions shall apply unless otherwise indicated. For the purposes of the present invention, the chemical elements are described in the periodic table of elements, CAS version and handbook of chemicals, 75,thed, 1994. In addition, the general principles of Organic Chemistry are described in "Organic Chemistry," Thomas Sorrell, University Science Books, Sausaltio: 1999, and "March's Advanced Organic Chemistry," by Michael B.Smith and Jerry March, John Wiley&Sons, New York, 2007, all of which are hereby incorporated by reference.
As described herein, the compounds of the present invention may be optionally substituted with one or more substituents, such as those of the above general formula, or as specifically exemplified, sub-classes, and groups encompassed by the present inventionA compound (I) is provided. In general, the term "substituted" indicates that one or more hydrogen atoms in a given structure are replaced with a particular substituent. Unless otherwise indicated, an optional substituent group may have one substituent substituted at each substitutable position of the group. When more than one position in a given formula can be substituted with one or more substituents selected from a particular group, the substituents may be substituted at each position, identically or differently. Wherein the substituent can be, but is not limited to, deuterium, F, Cl, Br, OH, C1-6Alkyl radical, C1-6Substituted by a substituent of alkoxy.
In the various parts of this specification, substituents of the disclosed compounds are disclosed in terms of group type or range. It is specifically intended that the invention includes each and every independent subcombination of the various members of these groups and ranges. For example, the term "C1-6Alkyl "means in particular independently disclosed methyl, ethyl, C3Alkyl radical, C4Alkyl radical, C5Alkyl and C6An alkyl group.
The term "alkyl" as used herein includes saturated straight or branched chain monovalent hydrocarbon radicals of 1 to 6 carbon atoms, wherein the alkyl radical may independently be optionally substituted with one or more substituents described herein. In some embodiments, the alkyl group contains 1 to 6 carbon atoms, in other embodiments, the alkyl group contains 1 to 4 carbon atoms, and in yet other embodiments, the alkyl group contains 1 to 3 carbon atoms. Further examples of alkyl groups include, but are not limited to, methyl (Me, -CH)3) Ethyl (Et-CH)2CH3) N-propyl (n-Pr, -CH)2CH2CH3) Isopropyl (i-Pr, -CH (CH)3)2) N-butyl (n-Bu, -CH)2CH2CH2CH3) 2-methylpropyl or isobutyl (i-Bu, -CH)2CH(CH3)2) 1-methylpropyl or sec-butyl (s-Bu, -CH (CH)3)CH2CH3) T-butyl (t-Bu, -C (CH)3)3) N-pentyl (-CH)2CH2CH2CH2CH3) 2-pentyl (-CH (C)H3)CH2CH2CH3) 3-pentyl (-CH (CH)2CH3)2) 2-methyl-2-butyl (-C (CH)3)2CH2CH3) 3-methyl-2-butyl (-CH (CH)3)CH(CH3)2) 3-methyl-1-butyl (-CH)2CH2CH(CH3)2) 2-methyl-1-butyl (-CH)2CH(CH3)CH2CH3) N-hexyl (-CH)2CH2CH2CH2CH2CH3) 2-hexyl (-CH (CH)3)CH2CH2CH2CH3) 3-hexyl (-CH (CH)2CH3)(CH2CH2CH3) 2-methyl-2-pentyl (-C (CH))3)2CH2CH2CH3) 3-methyl-2-pentyl (-CH (CH)3)CH(CH3)CH2CH3) 4-methyl-2-pentyl (-CH (CH)3)CH2CH(CH3)2) 3-methyl-3-pentyl (-C (CH)3)(CH2CH3)2) 2-methyl-3-pentyl (-CH (CH)2CH3)CH(CH3)2)2, 3-dimethyl-2-butyl (-C (CH)3)2CH(CH3)2) 3, 3-dimethyl-2-butyl (-CH (CH)3)C(CH3)3) And so on.
The term "alkenyl" denotes a straight or branched chain monovalent hydrocarbon radical of 2 to 6 carbon atoms, wherein at least one C-C is sp2Double bonds, wherein the alkenyl group may be independently optionally substituted with one or more substituents as described herein, include groups defined by "trans", "cis" or "E" and "Z", wherein specific examples include, but are not limited to, vinyl (-CH ═ CH)2) Allyl (-CH)2CH＝CH2) And so on.
The term "alkoxy" means an alkyl group attached to the rest of the molecule through an oxygen atom, wherein the alkyl group has the meaning as described herein. In some embodiments, alkoxy groups contain 1 to 6 carbon atoms; in other embodiments, the alkoxy group contains 1 to 4 carbon atoms; in still other embodiments, alkoxy groups contain 1-3 carbon atoms. The alkoxy group may be optionally substituted with one or more substituents described herein.
Examples of alkoxy groups include, but are not limited to, methoxy (MeO, -OCH)3) Ethoxy (EtO, -OCH)2CH3) 1-propoxy (n-PrO, n-propoxy, -OCH)2CH2CH3) 2-propoxy (i-PrO, i-propoxy, -OCH (CH)3)2) 1-butoxy (n-BuO, n-butoxy, -OCH)2CH2CH2CH3) 2-methyl-l-propoxy (i-BuO, i-butoxy, -OCH)2CH(CH3)2) 2-butoxy (s-BuO, s-butoxy, -OCH (CH)3)CH2CH3) 2-methyl-2-propoxy (t-BuO, t-butoxy, -OC (CH)3)3) 1-pentyloxy (n-pentyloxy, -OCH)2CH2CH2CH2CH3) 2-pentyloxy (-OCH (CH)3)CH2CH2CH3) 3-pentyloxy (-OCH (CH))2CH3)2) 2-methyl-2-butoxy (-OC (CH))3)2CH2CH3) 3-methyl-2-butoxy (-OCH (CH)3)CH(CH3)2) 3-methyl-l-butoxy (-OCH)2CH2CH(CH3)2) 2-methyl-l-butoxy (-OCH)2CH(CH3)CH2CH3) And so on.
The terms "alkylamino" and "alkylamino" are used interchangeably and include "N-alkylamino" and "N, N-dialkylamino" in which the hydrogen atoms in the amino groups are each independently substituted with one or two alkyl groups. Wherein, in some embodiments, the alkylamino group is one or two C1-12The alkyl group is attached to a nitrogen atom to form a lower alkylamino group. In other embodiments, alkylamino is one or two C1-6The alkyl group is attached to a nitrogen atom to form a lower alkylamino group. In other embodiments, alkylamino is one or moreTwo C1-4The alkyl group is attached to a nitrogen atom to form a lower alkylamino group. In still other embodiments, the alkylamino group is one or two C1-3The alkyl group is attached to a nitrogen atom to form a lower alkylamino group. Suitable alkylamino groups can be monoalkylamino or dialkylamino, and examples of alkylamino include, but are not limited to, N-methylamino, N-ethylamino, N-dimethylamino, N-diethylamino, and the like.
The term "alkynyl" refers to a straight or branched chain monovalent hydrocarbon radical containing 2 to 6 carbon atoms, at least one of which is a sp triple bond, wherein the alkynyl radical may independently be optionally substituted with one or more substituents described herein, in which some embodiments the alkyl radical contains 2 to 6 carbon atoms, and in which other embodiments the alkyl radical contains 2 to 4 carbon atoms. Specific examples include, but are not limited to, ethynyl (-C ≡ CH), propargyl (-CH)2C ≡ CH), propynyl (-C ≡ C-CH)3) Acetylenic butyl (-CH)2CH2C≡CH、-CH2C≡CCH3、-C≡CCH2CH3and-CH (CH)3) C ≡ CH) and alkynylpentyl (-CH)2CH2CH2C≡CH、-CH2CH2C≡CCH3、-CH2C≡CCH2CH3、-C≡CCH2CH2CH3、-CH2CH(CH3)C≡CH、-CH(CH3)CH2C≡CH、-C(CH3)2C≡CH、-CH(CH3)C≡CCH3and-C ≡ CCH (CH)3)2) And so on.
The term "cycloalkyl" denotes a monovalent or polyvalent saturated monocyclic, bicyclic or tricyclic ring system containing from 3 to 9 carbon atoms. In one embodiment, the cycloalkyl group contains 3 to 9 carbon atoms; in another embodiment, cycloalkyl contains 3 to 8 carbon atoms; in another embodiment, cycloalkyl groups contain 3 to 7 carbon atoms; in still other embodiments, the cycloalkyl group contains 3 to 6 carbon atoms. The cycloalkyl groups may be independently unsubstituted or substituted with one or more substituents described herein.
The term "n-atomic" where n is an integer typically describes the number of ring-forming atoms in a molecule in which the number of ring-forming atoms is n. For example, piperidinyl is a heterocyclic group consisting of 6 ring atoms.
The term "heterocyclyl" refers to a mono-, bi-or tricyclic ring system containing 3 to 9 ring atoms, which is non-aromatic, saturated or partially unsaturated, monovalent or multivalent, wherein at least one ring atom is selected from nitrogen, sulfur or oxygen atoms. Wherein said heterocyclyl group may be optionally substituted with one or more substituents as described herein. Unless otherwise specified, heterocyclyl may be carbon-or nitrogen-based, and-CH2-a group may optionally be replaced by-C (═ O) -or-C (═ S) -. The sulfur atom of the ring may optionally be oxidized to the S-oxide. The nitrogen atoms of the ring may optionally be oxidized to the N-oxide. In some embodiments, heterocyclyl is a heterocyclyl consisting of 3-9 ring atoms. In some embodiments, heterocyclyl is a heterocyclyl consisting of 5-9 ring atoms. In some embodiments, heterocyclyl is a heterocyclyl consisting of 3-6 ring atoms. In some embodiments, heterocyclyl is a heterocyclyl consisting of 4-6 ring atoms. In some embodiments, heterocyclyl is a heterocyclyl consisting of 5-6 ring atoms. In other embodiments, heterocyclyl is a heterocyclyl consisting of 4 ring atoms. In other embodiments, heterocyclyl is a heterocyclyl consisting of 5 ring atoms. In still other embodiments, heterocyclyl is a heterocyclyl consisting of 6 ring atoms.
Examples of "heterocyclyl" include, but are not limited to, pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, thialkyl, piperazinyl, and the like.
The term "heteroatom" means one or more of O, S, N, P and Si, including N, S and any oxidation state form of P; primary, secondary, tertiary amines and quaternary ammonium salt forms; or a form in which a hydrogen on a nitrogen atom in the heterocycle is substituted, for example, N (like N in 3, 4-dihydro-2H-pyrrolyl), NH (like NH in pyrrolidinyl) or NR (like NR in N-substituted pyrrolidinyl).
The term "halogen" or "halogen atom" refers to F, Cl, Br or I.
The term "aryl" denotes monocyclic, bicyclic and tricyclic carbon ring systems containing 6 to 10 ring atoms, or 6 to 9 ring atoms, or 6 to 8 ring atoms, wherein at least one ring system is aromatic, wherein each ring system contains 3 to 7 atoms in the ring and one or more attachment points to the rest of the molecule. Examples of the term aryl group may include phenyl, naphthyl and anthracenyl. The aryl group may independently be optionally substituted with one or more substituents described herein.
The term "heteroaryl" denotes monocyclic, bicyclic and tricyclic ring systems containing 5 to 10 ring atoms, or 5 to 8 ring atoms, or 9 to 10 ring atoms, or 9 ring atoms, or 5 to 6 ring atoms, wherein at least one ring is aromatic and at least one aromatic ring contains one or more heteroatoms, wherein each ring system contains a ring of 5 to 7 ring atoms with one or more attachment points to the rest of the molecule. In some embodiments, heteroaryl is a heteroaryl consisting of 5 to 10 ring atoms containing 1,2,3, or 4 heteroatoms independently selected from nitrogen, sulfur, and oxygen. In other embodiments, heteroaryl is a heteroaryl consisting of 5 to 9 ring atoms containing 1,2,3, or 4 heteroatoms independently selected from nitrogen, sulfur, and oxygen. In other embodiments, heteroaryl is a heteroaryl consisting of 9-10 ring atoms containing 1,2,3, or 4 heteroatoms independently selected from nitrogen, sulfur, and oxygen. In other embodiments, heteroaryl is heteroaryl consisting of 9 ring atoms containing 1,2,3, or 4 heteroatoms independently selected from nitrogen, sulfur, and oxygen. In other embodiments, heteroaryl is a heteroaryl consisting of 5 to 6 ring atoms containing 1,2,3, or 4 heteroatoms independently selected from nitrogen, sulfur, and oxygen. And the heteroaryl group may be substituted or unsubstituted, wherein the substituent may be, but is not limited to, deuterium, F, Cl, Br, OH, C1-6Alkyl radical, C1-6An alkoxy group.
Unless otherwise indicated, the structural formulae depicted herein include all isomeric forms (e.g., enantiomers, diastereomers, and geometric isomers (or conformers): for example, the R, S configuration containing an asymmetric center, (Z), (E) isomers of double bonds, and (Z), (E) conformers.
The term "prodrug", as used herein, represents a compound that is converted in vivo to a compound of formula (I). Such conversion is effected by hydrolysis of the prodrug in the blood or by enzymatic conversion to the parent structure in the blood or tissue. The prodrug compound of the invention can be ester, and in the prior invention, the ester can be used as the prodrug and comprises phenyl ester and aliphatic (C)1-24) Esters, acyloxymethyl esters, carbonates, carbamates and amino acid esters. For example, a compound of the present invention contains a hydroxy group, i.e., it can be acylated to provide the compound in prodrug form. Other prodrug forms include phosphate esters, such as those obtained by phosphorylation of a hydroxyl group on the parent. For a complete discussion of prodrugs, reference may be made to the following: T.Higuchi and V.Stella, Pro-drugs as Novel Delivery Systems, Vol.14of the A.C.S.Symphosis Series, Edward B.Roche, ed., Bioreproducible Carriers in Drug designs, American Pharmaceutical Association and Pergamon Press,1987, J.Rautio et al, Prodrugs: Design and Clinical Applications, Nature Review Drug Discovery,2008,7, 255-.
Unless otherwise indicated, all tautomeric forms of the compounds of the invention are included within the scope of the invention. In addition, unless otherwise indicated, the structural formulae of the compounds described herein include isotopically enriched concentrations of one or more different atoms.
"metabolite" refers to the product of a particular compound or salt thereof obtained by metabolism in vivo. Metabolites of a compound can be identified by techniques well known in the art, and its activity can be characterized by assay methods as described herein. Such products may be obtained by administering the compound by oxidation, reduction, hydrolysis, amidation, deamidation, esterification, defatting, enzymatic cleavage, and the like. Accordingly, the present invention includes metabolites of compounds, including metabolites produced by contacting a compound of the present invention with a mammal for a sufficient period of time.
The definition and convention of stereochemistry in the present invention is generally used with reference to the 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., "stereoschemistry of Organic Compounds", John Wiley & Sons, Inc., New York,1994. All stereoisomeric forms of the compounds of the present invention, including, but in no way limited to, diastereomers, enantiomers, atropisomers, and mixtures thereof, such as racemic mixtures, form part of the present invention. Many organic compounds exist in optically active form, i.e., they have the ability to rotate the plane of plane polarized light. In describing optically active compounds, the prefix D, L or R, S is used to indicate the absolute configuration of the chiral center of the molecule. The prefixes d, l or (+), (-) are used to designate the sign of the rotation of plane polarized light of the compound, with (-) or l indicating that the compound is left-handed and the prefix (+) or d indicating that the compound is right-handed. The chemical structures of these stereoisomers are identical, but their stereo structures are different. A particular stereoisomer may be an enantiomer, and a mixture of isomers is commonly referred to as a mixture of enantiomers. 50: 50 is called a racemic mixture or racemate, which may result in no stereoselectivity or stereospecificity during the chemical reaction. The terms "racemic mixture" and "racemate" refer to a mixture of two enantiomers in equimolar amounts, lacking optical activity.
The term "tautomer" or "tautomeric form" means that isomers of structures of different energies may be interconverted through a low energy barrier. For example, proton tautomers (i.e., prototropic tautomers) include tautomers that move through protons, such as keto-enol and imine-enamine isomerizations. Valence (valence) tautomers include tautomers that recombine into bond electrons. Unless otherwise indicated, all tautomeric forms of the compounds of the invention are within the scope of the invention.
As used herein, "pharmaceutically acceptable salts" refer to organic and inorganic salts of the compounds of the present invention. Pharmaceutically acceptable salts are well known in the art, as are: berge et al, description of the descriptive pharmaceutical acceptable salts in detail in J. pharmaceutical Sciences,66:1-19,1977. Pharmaceutically acceptable non-toxic acid salts include, but are not limited to, salts of inorganic acids such as hydrochlorides, hydrobromides, phosphates, sulfates, perchlorates, and salts of organic acids such as acetates, oxalates, maleates, tartrates, citrates, succinates, malonates, which are formed by reaction with amino groups, or which are obtained by other methods described in the literature, such as ion exchange. Other pharmaceutically acceptable salts include adipates, malates, 2-hydroxypropionates, alginates, ascorbates, aspartates, benzenesulfonates, benzoates, bisulfates, borates, butyrates, camphorates, camphorsulfonates, cyclopentylpropionates, digluconates, dodecylsulfates, ethanesulfonates, formates, fumarates, glucoheptonates, glycerophosphates, gluconates, hemisulfates, heptanoates, hexanoates, hydroiodiates, 2-hydroxy-ethanesulfonates, lactobionates, lactates, laurylsulfates, malates, malonates, methanesulfonates, 2-naphthalenesulfonates, nicotinates, nitrates, oleates, palmitates, embonate, pectinates, persulfates, 3-phenylpropionates, alginates, salts of alginic acid, salts of citric acid, malic acid, salts of lactic acid, lauryl sulfate, malic acid, malonic acid, salts of lactic acid, salts of lactic acid, salts of esters, salts of lactic acid, salts of esters, salts of acids, salts of lactic acid, salts of acids, salts of esters, salts of acids, salts of esters, salts of acids, salts of esters, salts of esters, salts of acids, salts of esters, salts of acids, salts of esters, salts of acids, salts of esters, salts of L, salts of acids, salts of esters, salts, Picrates, pivalates, propionates, stearates, thiocyanates, p-toluenesulfonates, undecanoates, pentanoates, and the like. Salts obtained with appropriate bases include alkali metals, alkaline earth metals, ammonium and N+(C1-4Alkyl radical)4A salt. The present invention also contemplates the combination of any group containing NQuaternary ammonium salts formed by the above-mentioned process. Water-soluble or oil-soluble or dispersion products can be obtained by quaternization. Alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Pharmaceutically acceptable salts further include suitable, non-toxic ammonium, quaternary ammonium salts and amine cations resistant to formation of counterions, such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, C1-8Sulfonates and aromatic sulfonates.
"solvate" of the present invention refers to an association of one or more solvent molecules with a compound of the present invention. Solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, aminoethanol. The term "hydrate" refers to an association of solvent molecules that is water.
In the present invention, when the structural formula has
Figure BDA0001845508230000161
Or the like, means that the covalent bond is in a position above or below the paper, but it is to be noted that this configuration has a relative meaning only, unless otherwise specified. Likewise, when referring to "cis" or "trans," only the relative positions of the groups are stated unless otherwise specified.
The compounds of formula (I) may also exist in other protected forms or derivatives which will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.
The present invention relates to said compounds and the use of said compounds for the treatment of bacterial infectious diseases in mammals caused by tuberculosis bacteria, in particular the invention is also applicable for the treatment of tuberculosis caused by tuberculosis infection.
The invention encompasses pharmaceutical compositions comprising a therapeutic amount of a compound of the invention, and one or more pharmaceutically acceptable carriers and/or excipients. Carriers include, for example, saline, buffered saline, dextrose, water, glycerol, ethanol, and combinations thereof, as discussed in more detail below. The composition may also contain minor amounts of wetting or emulsifying agents, or pH buffering agents, if desired. The composition may be a liquid solution, suspension, emulsion, tablet, pill, capsule, sustained release formulation or powder. The composition can be formulated into suppository with conventional binder and carrier such as triglyceride. Oral formulations may include standard carriers such as pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharine, cellulose and magnesium carbonate, and the like. Depending on the desired formulation, formulation may involve mixing, granulating and compressing or dissolving the ingredients. In another approach, the composition may be formulated as nanoparticles.
The pharmaceutical carrier used may be either a solid or a liquid.
The carrier or excipient may comprise a time delay material known in the art, such as glyceryl monostearate or glyceryl distearate, and may also comprise a wax, ethylcellulose, hydroxypropylmethylcellulose, methylmethacrylate, or the like. When the formulation is intended for oral administration, it is recognized that 0.01% tween 80 in phostapg-50 (phosphoipid and 1, 2-propanediol concentrate, a. nattermann & cie. gmbh) is used in the formulation of acceptable oral formulations for other compounds, and may be adapted to the formulation of various compounds of the invention.
A wide variety of pharmaceutical forms can be used in administering the compounds of the present invention. If a solid carrier is used, the preparation may be in the form of a tablet, powder or pellet placed in a hard gelatin capsule or in the form of a lozenge or troche. The amount of solid carrier varies widely, but is preferably from about 25mg to about 1 g. If a liquid carrier is used, the preparation may be in the form of a syrup, emulsion, soft gelatin capsule, sterile injectable solution or suspension in an ampoule or vial or in a nonaqueous liquid suspension.
Various delivery systems are known and may be used for the administration of the compounds or various formulations thereof, including tablets, capsules, injectable solutions, capsules in liposomes, microparticles, microcapsules, and the like. Methods of introduction include, but are not limited to, cutaneous, intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, pulmonary, epidural, ocular and (generally preferred) oral routes. The compounds may be administered by any convenient or other suitable route, for example by infusion or bolus injection, by absorption via the epithelial or mucosal route (e.g., oral mucosa, rectal and intestinal mucosa, etc.) or by drug-loaded stents and may be administered with other biologically active agents. Can be administered systemically or locally. For use in the treatment or prevention of a nasal, bronchial or pulmonary disorder, the preferred route of administration is oral, nasal or bronchial aerosol or nebulizer.
General synthetic methods
In general, the compounds of the invention can be prepared by the methods described herein, unless otherwise indicated, wherein the definitions of the substituents are given above. The following reaction schemes and examples serve to further illustrate the context of the invention.
Those skilled in the art will recognize that: the chemical reactions described herein may be used to suitably prepare a number of other compounds of the invention, and other methods for preparing the compounds of the invention are considered to be within the scope of the invention. For example, the synthesis of those non-exemplified compounds according to the present invention can be successfully accomplished by those skilled in the art by modification, such as appropriate protection of interfering groups, by the use of other known reagents in addition to those described herein, or by some routine modification of reaction conditions. In addition, the reactions disclosed herein or known reaction conditions are also recognized as being applicable to the preparation of other compounds of the present invention.
The examples described below, unless otherwise indicated, all temperatures are in degrees Celsius (. degree. C.). Reagents for the experiments were purchased from Beijing coupling technologies, Inc., Bailingwei technologies, Inc., Acros Organics, Alfa Aesar, Sigma-Aldrich, and TCI, unless otherwise specified, and used without purification. The solvents used in the experiments were purchased mainly from Beijing chemical plant and Shigaku chemical Co., Ltd, and were used without further treatment except for THF and DMF which were further treated by the solvent purification system of VAC corporation. GF254Thin layer chromatography silica gel plates, GF254Silica gel thick preparation plate and silica gel powder (60-100 meshes) for column chromatography160-.
HPLC-MS analyzer: the HPLC analyzer was an Agilent 1100HPLC system, an Agilent G1312A pump, an Agilent G1314A UV detector, an Agilent G1313A autosampler, an Agilent G1316A column oven and a diverter valve. The column was a Kromasil C18 analytical column (4.6 μm,4.6 mm. times.50 mm) available from DIKMA. The mobile phase was acetonitrile containing 0.05% HCOOH and water. Linear gradient elution 5:95(v: v) acetonitrile-H2O to 95:5(v: v) acetonitrile-H2O, time 5minutes, flow rate 1 mL/min. UV detection wavelength 254 nm. ThermoFinnigan LCQ-
An Advantage mass spectrometer, 5% of the eluent is shunted into the mass spectrometer, and an electrospray ion source (ESI) is adopted in a positive ion or negative ion scanning mode. The method is mainly used for reaction monitoring and primary determination of compound purity.
UPLC-MS analyzer: the Acquity UPLC-MS system of Waters corporation includes a binary solvent manager, a sample manager, a chromatography column manager, a PDA detector, and an SQ mass spectrometer. The chromatographic column is Acquisty of Waters corporation
Figure BDA0001845508230000171
BEH C18 column (1.7 μm,2.1 mm. times.50 mm). The mobile phase was acetonitrile containing 0.05% HCOOH and water. Linear gradient elution 5:95(v: v) acetonitrile-H2O to 95:5(v: v) acetonitrile-H2O, time 3minutes, flow rate 0.3 mL/min. UV detection wavelength 254 nm. The SQ mass spectrometer adopts a positive ion or negative ion scanning mode and an electrospray ionization source (ESI). The method is mainly used for reaction monitoring and primary determination of compound purity.
HPLC analyzer: an Agilent 1260HPLC system, an Agilent G1311C quaternary pump, an Agilent G4212B ultraviolet detector, an Agilent G1367E high-performance autosampler, and an Agilent G1316A column oven. A chiral analytical column: DAICEL CHIRALPAK AD-H, 250X 4.6mm, 5. mu.M (manufactured by DAICEL, Daiiol, Japan). The mobile phase is n-hexane/isopropanol and is eluted at equal intervals. UV detection wavelength 254 nm. The method is mainly used for optical degree analysis of target compounds.
High resolution mass spectrometer: agilent LC/MSD TOF system.A chromatographic column: AgilentZORBAX SB-C18 (Rapidesolution, 3.5 μm, 2.1X 30 mm). Mobile phase: MeOH H2O75: 25(v: v), containing 5mmol/L formic acid, isocratically eluted. The time is 5min, and the flow rate is 0.40 mL/min. The mass spectrum detection adopts a positive ion scanning mode and an electrospray ionization source (ESI). The method is mainly used for determining the accurate molecular weight of a target compound.
Nuclear magnetic resonance apparatus: bruker Avance 400MHz, solvent CDCl3,DMSO-d6,Acetone-d6or Methanol-d4。
Melting point apparatus: yanaco micro melting point apparatus, OptiMelt melting point apparatus, were not calibrated.
The following acronyms are used throughout the invention:
DMF dimethyl formamide
POCl3Phosphorus oxychloride
MOM methoxymethyl group
DMSO dimethyl sulfoxide
NH4Cl ammonium chloride
THF tetrahydrofuran
NaBH3CN Cyanoborohydride sodium salt
AlCl3Aluminium chloride
HgCl2Mercuric chloride
ZnCl2Zinc chloride
NH4Br ammonium Bromide
Oxone potassium peroxymonosulfonate
F-TEDA-BF41-chloromethyl-4-fluoro-1, 4-diazabicyclo [2.2.2]Octane bis (tetrafluoroborate) salt
SO2Cl2Sulphonyl chlorides
CuCN cuprous cyanide
BF3·Et2Boron trifluoride diethyl etherate
TBAF.3H2O-tetrabutylammonium fluoride trihydrate
PPh3 Triphenylphosphine
DDQ 2, 3-dichloro-5, 6-dicyano-1, 4-benzoquinone
DIPEA N, N-diisopropylethylamine
NBS N-bromosuccinimide
BOPCl bis (2-oxo-3-oxazolidinyl) phosphoryl chloride
AIBN azobisisobutyronitrile
AIVN azobisisoheptonitrile
pHGFP transfection of pH-sensitive Green fluorescent protein
BCG vaccine
BCG of BCG-pHGFP transfection pH sensitive green fluorescent protein plasmid
H37Rv-pHGFP transfected pH sensitive Green fluorescent protein plasmid H37Rv strains
MOMCl chloromethyl methyl ether
TsCl tosyl chloride
DCM dichloromethane
NCS N-chlorosuccinimide
HOSU N-hydroxysuccinimide
TEA Triethylamine
EDC.HCl, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride
FBS bovine fetal serum
CFU colony Forming Unit
MDR-TB multi-drug resistant tuberculosis
XDR-TB extensively drug-resistant tuberculosis
The synthesis method comprises the following steps: wherein each substituent has the meaning as described in the present invention.
In some embodiments of the present invention, methods of preparing compounds of formula (I) are disclosed, comprising the following scheme:
route 1: synthetic route and conditions of intermediate
Figure BDA0001845508230000191
Reaction conditions are as follows:
(a) phloroglucinol is used as a starting material, and is subjected to Vilsmeier-Haack formylation (such as DMF and phosphorus oxychloride, oxalyl chloride and DMF) by using an aprotic solvent (such as dioxane, ethyl acetate and THF) in an equivalent ratio of 1:1, wherein the reaction temperature is room temperature or heating, preferably heating.
(b) And (4) reducing benzoyl. The intermediate is reduced to methyl under the condition of a reducing agent, preferably NaBH3CN, an aprotic solvent (such as THF) and protonic acid are used for adjusting the pH of the reaction solution to 4-5.
(c) And F-C acylation. The intermediate reacts with acetyl chloride with different substitutions under the catalysis of Lewis acid to prepare the 2,4, 6-trihydroxy-3-methyl benzophenone (or benzaldehyde) intermediate. Preferably, the Lewis acid is AlCl3(ii) a Carrying out reaction in an equivalent weight ratio of 1: 1.2; the reaction temperature is heating, preferably 50 ℃.
(d) And selectively protecting phenolic hydroxyl. The protecting group is preferably MOM, and the equivalent is the number equivalent of the phenolic hydroxyl to be protected; the solvent is DMF, DMSO, acetone, preferably acetone; simultaneously adding alkali (such as sodium hydrogen, sodium bicarbonate and sodium carbonate) with equivalent of the number of the phenolic hydroxyl group to be protected, preferably sodium carbonate; the reaction temperature is preferably room temperature, and the reaction time depends on the specific reaction condition.
(e) And (4) protecting phenolic hydroxyl. The protecting group is preferably methyl; 2 times of equivalent of alkali and dimethyl sulfate are added, the reaction temperature is reflux, and the reaction time is determined according to specific reaction conditions.
(f) And (4) removing the protecting group. The solvent is a protic solvent (e.g., alcohol, water), preferably methanol. Protonic acid is also needed as a catalyst, such as hydrochloric acid, sulfuric acid and the like, and the acid is 2 times equivalent; the reaction temperature is reflux, and the reaction time is determined according to specific reaction conditions and is generally 2 to 3 hours.
(g) Bis-formylation of phloroglucinol. The conditions are the same as a, except that the formylation reagent is 2 times equivalent.
(h) And (4) reducing benzoyl. The reducing agent is preferably Zn/HgCl2The solvent is an aprotic solvent (e.g., dioxane); at the same time, 0.5 equivalent of acid is added for catalysis, and concentrated hydrochloric acid is preferably used.
(i) And (4) activation of benzene ring carbon. Generally, N, N, N ', N' -tetramethylmethanediamine is used as an activating agent with 1.2 times of equivalent; the solvent is an aprotic solvent, preferably dichloromethane; the reaction temperature is room temperature and the reaction time is generally 0.5 h.
(j) And (3) substitution of benzene ring. When the substituent is bromine, the proviso is NH4Br is a bromine source, Oxone is an oxidant, and the reaction is carried out at room temperature for 3 hs; when the substituent is fluorine, provided that F-TEDA-BF4Is a fluorine source, and the reaction temperature is-45 ℃ to 0 ℃. When the substituent is chlorine, the proviso is SO2Cl2Reacting for 3 hours at room temperature as a chlorine source; when the substituent is cyano, with the proviso that i) NH4Br,Oxone,rt；ii)CuCN,DMF,130℃。
Route 2: synthetic route and conditions of intermediate
Figure BDA0001845508230000201
Reaction conditions are as follows:
(a) triethyl phosphonoacetate and different substituted ketones are used as substrates, sodium hydrogen as base and THF as solvent, the temperature is 0 ℃, and the reaction time is 5 h.
(b) And (3) hydrolyzing the ester. 2 times the amount of a base, preferably potassium hydroxide; the solvent is alcohol or THF, preferably methanol; 80 ℃ and 20 h.
(c) And (5) constructing a chromanone ring. Lewis acid catalysis, typically aluminium trichloride and BF3·Et2O, preferably BF3·Et2O; the reaction temperature is 50-70 ℃, and preferably 70 ℃; the time is 3 h.
(d) And F-C acylation. The reaction conditions are as in scheme 1, c, the Lewis acid is preferably BF3·Et2O。
(e) And selectively protecting phenolic hydroxyl. The reaction conditions are the same as those in scheme 1.
(f) And (5) constructing a chromanone ring. And (3) methyl sources: paraformaldehyde, aqueous formaldehyde, acetals, preferably paraformaldehyde; a large excess of base, preferably 10-fold equivalent, preferably organic base diethylamine, needs to be added; the solvent is a protic solvent, preferably ethanol; refluxing; and 3 d.
(g) And (4) removing the protecting group. The reaction conditions are the same as in scheme 1.
(h) And (3) hydroximes. Hydroxylamine hydrochloride; sodium carbonate is used as alkali; methanol is used as a solvent; room temperature; and 3 h.
(i) And (3) reducing carbonyl. The reducing agent is generally sodium cyanoborohydride, sodium borohydride, zinc powder and the like, and preferably zinc powder; the reaction should be carried out under acidic conditions, preferably with concentrated hydrochloric acid adjusted to 2-3; the temperature is 0-normal temperature. The time is 5 h.
(j) And selectively protecting phenolic hydroxyl. The reaction conditions are as in scheme 1, e, and the protecting group is preferably Ts.
(k) And (4) protecting phenolic hydroxyl. The reaction conditions are as in e of scheme 1.
(l) And (4) removing the protecting group. The reaction condition is TBAF.3H2O, THF, normal temperature, 5 h.
(m) activation of benzene ring carbons. The reaction conditions are the same as in scheme 1.
(n) construction of isoxazole rings. The reaction conditions are PPh3And DDQ is an oxidant, dichloromethane is a solvent, room temperature, 4 h.
(o) reductive amination of aniline. Using different substituted ethyl acetoacetate as an acylation reagent; the reducing agent is generally selected from sodium cyanoborohydride; the acid is a catalyst, typically an organic protic acid, preferably acetic acid; the aprotic solvent is a solvent, preferably dichloroethane; room temperature, 24 h.
(p) construction of 2, 3-dihydroquinolinone Ring. Is prepared by adopting acetic acid solution of hydrobromic acid at high temperature. The preferred temperature is 140 ℃ and the reaction time is generally 7h, depending on the particular reaction.
(q) substitution of the phenyl ring. The reaction conditions are as in scheme 1.
(r)1) refluxing acetic anhydride and sodium acetate; 2) and refluxing the sodium carbonate aqueous solution.
(s) NBS, tetrahydrofuran, Normal temperature, 1 h.
Route 3: synthetic route and conditions of intermediate
Figure BDA0001845508230000211
Reaction conditions are as follows:
(a) and F-C acylation. The reaction conditions are the same as in c of scheme 1.
(b) And (4) protecting phenolic hydroxyl. Acetyl is chosen as a protecting group, typically acetyl chloride or acetic anhydride is used as the acetyl source, preferably acetic anhydride; the base is selected from common organic bases such as triethylamine, DIPEA, pyridine, preferably DIPEA. Dichloromethane or THF as solvent, room temperature 20 h.
(c) And (3) benzyl bromination. The bromine source can be NBS, amine bromide, bromine simple substance, preferably NBS; the free radical initiator is BOPCl, AIBN, AIVN, preferably AIBN; selecting carbon tetrachloride as a solvent; 40 ℃; and 4 h.
(d) And (4) removing the protecting group. The solvent is generally selected from protic solvents, such as methanol; the acid is selected from protonic acid, preferably sulfuric acid; the temperature is from room temperature to 50 ℃, preferably 50 ℃; and 3 h.
(e) And (3) substitution of benzene ring. The reaction conditions are as in scheme 1.
(f) And (3) constructing a benzhydryl group. Provided that i) R4＝H,RCHO,CH3COOH,rt；ii)R4＝CH2N(CH3)2,ZnCl2And dioxane, reflux.
(g) And (3) constructing a benzo ether ring. The solvent is DMF, DMSO, acetone, ethyl acetate, dioxane. The base is sodium bicarbonate, sodium carbonate, potassium carbonate or cesium carbonate. The preferred combination is acetone, cesium carbonate, 5h, room temperature.
Route 4: synthetic route and conditions of intermediate
Figure BDA0001845508230000212
Reaction conditions are as follows:
(a) construction of chromanone. The raw materials are phloroglucinol and various substituted ethyl acetoacetate; the acid is protonic acid or Lewis acid, and phosphorus oxychloride is preferred; the solvent is protic alcohol, such as methanol and ethanol. The temperature is from room temperature to 85 ℃, preferably 85 ℃; and 3 h.
(b) And F-C acylation. Acetic anhydride as a source of acetyl; nitromethane is used as a solvent, and raw materials of coumarin and nitromethane react according to an equivalent weight of a molar ratio of 1: 7; preferably, the Lewis acid is AlCl3(ii) a The reaction temperature is heating, preferably 110 ℃; and (4) 1 h.
(c) Bromination of benzene ring. The reaction is carried out at normal temperature under the conditions of NBS and dichloromethane serving as a solvent.
Route 5: synthetic route and conditions for target compound
Figure BDA0001845508230000213
Reaction conditions are as follows:
and (3) constructing a benzhydryl group. Provided that i) R16＝H,R13CHO,CH3COOH,rt；ii)R16＝CH2N(CH3)2,ZnCl 21, 4-dioxane, refluxing.
Two methods are generally used for the ligation of two fragments, method one: generating a target product in the presence of an aldehyde and a protonic acid; however, since the reactivity of the two fragment reaction sites is not the same, there are by-products of partial monomer polymerization during the reaction. The second method comprises the following steps: dimethylamine fragment is used as leaving group to activate reaction site, and a target product is generated with high yield under the catalysis of Lewis acid, and the method has the characteristics that: dimethylamine fragments are adopted to activate reaction sites, so that a byproduct of monomer polymerization is avoided, and a target product can be prepared with high yield by Lewis acid catalysis.
The following describes embodiments of the present invention in detail.
Example 11- (3- (3-butanoyl-2, 6-dihydroxy-4-methoxy-5-methylbenzyl) -2,4, 6-trihydroxy-5-methylphenyl) -2-methylbutan-1-one
Figure BDA0001845508230000221
2,4, 6-trihydroxybenzaldehyde (1)
DMF (15mmol) was weighed into a round-bottomed flask, and POCl was slowly dropped under ice bath3(15mmol), after dropping, stirring at room temperature for 30 min. The DMF and POCl were mixed in an ice bath3Slowly dripping the reaction solution into 6mL of 1, 4-dioxane solution of phloroglucinol (15mmol), stirring at room temperature for 2h, stopping the reaction, pouring the reaction solution into 100mL of ice water, standing, filtering after crystal precipitation to obtain 11.867g of orange-red needle-shaped crystals, and obtaining the yield: 80.8 percent of the total weight of the steel,1H-NMR(300MHz,DMSO-d6)δ11.46(s,2H),10.65(s,1H),9.912(s,1H),5.78(s,2H)。
2,4, 6-Trihydroxytoluene (2)
Dissolving the intermediate 1(10.04mmol) in 200mL of THF, adding sodium cyanoborohydride (50mmol) under stirring, immediately turning the reaction liquid from orange red to white, then gradually turning yellow, dropwise adding 2N HCl into the reaction liquid at the moment, immediately turning white the solution, then gradually turning yellow, dropwise adding 2N HCl in time until the reaction liquid does not turn yellow, continuing stirring at room temperature for 1h, stopping the reaction, filtering, concentrating under reduced pressure, extracting, concentrating under reduced pressure, and performing silica gel column chromatography (petroleum ether/ethyl acetate is 5:1) to obtain a white solid 2, wherein the yield is as follows: 68.3 percent of the total weight of the mixture,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 butanone (3)
To 1, 2-dichloroethane (6mL) was added AlCl3(14.96mmol), butyryl chloride (7.48mmol) was added under stirring at room temperature, intermediate 2(6.8mmol) was added after 10min, reaction was stopped after 50 ℃ for 1h, cooling was performed, the mixture was poured into dilute hydrochloric acid containing ice, stirring was performed for 5min, ethyl acetate was extracted, concentration was performed under reduced pressure, and silica gel column chromatography (DCM/MeOH ═ 100:1) gave 3 as a pale yellow solid, yield: 85 percent of the total weight of the mixture,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 methoxy phenyl butanone (4)
Intermediate 3(7.14mmol) was dissolved in 140mL of acetone, potassium carbonate (53.5mmol) was added at room temperature with stirring, and the mixture was stirredAfter 2min, MOMCl (17.85mmol) was added, the reaction was stopped after 1h, the filtrate was filtered, concentrated under reduced pressure, and silica gel column chromatography (petroleum ether/ethyl acetate ═ 30:1) gave 4 as a white solid in yield: 89 percent of the total weight of the mixture,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-methoxy-4, 6-dimethoxymethoxy) -3-methylbenzyl butanone (5)
Adding potassium carbonate (15mmol) into an acetone solution (20mL) of the intermediate 4(5mmol) at room temperature, stirring for 2min, dropwise adding dimethyl sulfate (15mmol), stirring for 5min, refluxing until the reaction is complete, filtering, concentrating the filtrate under reduced pressure, and performing silica gel column chromatography (petroleum ether/ethyl acetate ═ 30:1) to obtain a colorless oily substance 5, wherein the yield is as follows: the content of the active carbon is 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-methoxy-3-methylbenzyl butanone (6)
To a solution of intermediate 5(3mmol) in methanol (5mL) at room temperature was added 0.5mL concentrated hydrochloric acid, refluxed for 1h, cooled, concentrated under reduced pressure, and subjected to silica gel column chromatography (petroleum ether/ethyl acetate ═ 20:1) to give 6 as a pale yellow solid in yield: in the proportion of 93%,1H-NMR(300MHz,DMSO-d6)δ12.30(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-Trihydroxyl-3-methylbenzene (2-methyl) butanone (7)
The synthesis of reference intermediate 3 gave 7 as a pale yellow solid in yield: the content of the active carbon is 83 percent,1H-NMR(300MHz,DMSO-d6)δ14.10(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)。
dissolving intermediate 6(0.1mmol) and intermediate 7(0.1mmol) in 1mL of acetic acid, adding 10 drops of aqueous formaldehyde solution, stirring at room temperature for 8h, adding 5mL of ethyl acetate, washing with saturated aqueous sodium bicarbonate solution until no bubbling occurs, and extractingTaking, concentrating under reduced pressure, and performing silica gel column chromatography (petroleum ether/ethyl acetate 40:1) to obtain yellow solid powder, wherein the yield is as follows: 48 percent, mp 58-60 ℃,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。
example 21- (3- (3-butyryl-2, 4, 6-trihydroxy-5-methylbenzyl) -2, 4-dihydroxy-6-methoxy-5-methylphenyl) butan-1-one
Figure BDA0001845508230000231
Referring to the synthesis of example 1, the title compound was obtained from intermediate 3 and intermediate 6 as a brown powder in yield: 35 percent, mp 77-79 ℃,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。
example 33- (3-butyryl-2, 6-dihydroxy-4-methoxy-5-methylbenzyl) -2,4, 6-trihydroxy-5-methylbenzaldehyde
Figure BDA0001845508230000232
2,4, 6-trihydroxy-3-methylbenzaldehyde (8)
The synthesis procedure referenced for intermediate 1 gave 8 as a pale yellow solid in yield: 88 percent of the total weight of the mixture,1H-NMR(400MHz,DMSO-d6)δ12.32(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 synthesis of example 1, the title compound was obtained from intermediate 8 and intermediate 6 as a light yellow solid in yield: 61%, mp>210℃，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。
Example 45, 5' -bis (2,4, 6-trihydroxy-3-methylbenzaldehyde) methane
Figure BDA0001845508230000233
Referring to the synthesis of example 1, the title compound was obtained from intermediate 8 as a light yellow solid in yield: 24%, mp>256℃，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。
Example 51- (3- (3-acetyl-2, 4, 6-trihydroxy-5-methylbenzyl) -2, 4-dihydroxy-6-methoxy-5-methylphenyl) butan-1-one
Figure BDA0001845508230000234
2,4, 6-Trihydroxyl-3-methylacetophenone (9)
The synthesis of reference intermediate 3 gave 9 as a pale yellow solid in yield: 88%, yield: the content of the active carbon is 83 percent,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 synthesis of example 1, the title compound was obtained from intermediate 9 and intermediate 6 as a yellow solid in yield: 44%, mp 182-,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。
example 61- (2, 4-dihydroxy-6-methoxy-5-methyl-3- (2,4, 6-trihydroxy-3-isobutyryl-5-methylbenzyl) phenyl) butan-1-one
Figure BDA0001845508230000235
2,4, 6-Trihydroxyl-3-Methylbenzisobutyrone (10)
The synthesis of reference intermediate 3 gave a pale yellow solid 10, yield: 79 percent of the total weight of the mixture,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 synthesis of example 1, the title compound was obtained from intermediate 10 and intermediate 6 as a yellow solid in yield: 41%, mp 103-,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。
example 71- (3- (3-butanoyl-2, 6-dihydroxy-4-methoxy-5-methylbenzyl) -2,4, 6-trihydroxy-5-methylphenyl) -3-methylbutan-1-one
Figure BDA0001845508230000241
2,4, 6-Trihydroxyl-3-Methylbenz-i-pentanone (11)
The synthesis of reference intermediate 3 gave a yellow solid 11, yield: 77 percent of the total weight of the mixture,1H-NMR(400MHz,Acetone-d6)δ13.91(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 synthesis of example 1, the title compound was obtained from intermediate 11 and intermediate 6 as a yellow solid in yield: 37 percent, mp 189-,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。
example 81- (3- (3- (Cyclopropaneformyl) -2,4, 6-trihydroxy-5-methylbenzyl) -2, 4-dihydroxy-6-methoxy-5-methylphenyl) butan-1-one
Figure BDA0001845508230000242
2,4, 6-Trihydroxyl-3-methylbenzene (2-cyclopropyl) ketone (12)
The synthesis of reference intermediate 3 gave a yellow solid 11, yield: 68 percent of the total weight of the mixture,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 synthesis of example 1, the title compound was obtained from intermediate 12 and intermediate 6 as a yellow solid in yield: 40%, mp 168-,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。
example 91- (3- (3-butanoyl-2, 6-dihydroxy-4-methoxy-5-methylbenzyl) -2,4, 6-trihydroxy-5-methylphenyl) heptan-1-one
Figure BDA0001845508230000243
2,4, 6-Trihydroxyl-3-Methylbenzepinone (13)
The synthesis procedure referenced for intermediate 3 gave yellow solid 13, white solid, yield: the content of the active carbon is 58 percent,1H-NMR(400MHz,Acetone-d6)δ13.89(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 synthesis of example 1, the title compound was obtained from intermediate 13 and intermediate 6 as a light yellow solid in yield: 33 percent, mp 94-96 ℃,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)δ207.0,206.9,161.7,160.1,159.8,159.5,112.1,109.5,107.8,105.7,103.9,101.8,61.5,44.3,43.9,31.7,29.2,24.8,22.6,18.2,16.1,14.0,13.9,9.1,7.5.HRMS calcd for C24H29O8[M+H]+:489.24829；found:489.24826。
example 101- (3- ((6, 8-dihydroxy-9-methyl-5-propyl-2, 3-dihydrobenzo [ f ] [1,4] oxazepin-7-yl) methyl) -2, 4-dihydroxy-6-methoxy-5-methylphenyl) butan-1-one
Figure BDA0001845508230000244
2- (2-Boc amino) ethoxy-4, 6-dimethoxymethoxy-3-methylbenzyl butanone (14)
Intermediate 4(0.5mmol) and triphenylphosphine (1.25mmol) were dissolved in 2mL THF, N-Boc protected ethanolamine (1.25mmol) was added with stirring at room temperature, and then DEAD (1.25mmol) was slowly added dropwise, reacted for 15min, concentrated under reduced pressure, and subjected to silica gel column chromatography (petroleum ether/ethyl acetate ═ 20:1) to obtain colorless oil 14, yield: 79 percent of the total weight of the mixture,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 ] [1,4] oxazepan-6, 8-diol (15)
The synthesis procedure referenced for intermediate 6 gave 15 as a pale yellow solid in yield: 67% of the total weight of the steel,1H-NMR(300MHz,DMSO-d6)δ13.51(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 synthesis of example 1, the title compound was obtained from intermediate 15 and intermediate 6 as a yellow solid in yield: 27%, mp 111-,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。
example 113- (2, 6-dihydroxy-4-methoxy-3-methyl-5- (2-methylbutanoyl) benzyl) -2,4, 6-trihydroxy-5-methylbenzaldehyde
Figure BDA0001845508230000251
2-hydroxy-3-methyl-4, 6-dimethoxymethoxybenzene (2-methyl) butanone (16)
The synthesis procedure referenced for intermediate 4 gave 16 as a white solid in yield: 85 percent of the total weight of the mixture,1H-NMR(300MHz,DMSO-d6)δ13.38(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-methoxy-4, 6-dimethoxymethoxybenzene (2-methyl) butanone (17)
The synthesis procedure referenced for intermediate 5 gave 17 as a colorless oil, yield: 87 percent of the total weight of the mixture,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-methoxy-4, 6-dihydroxybenzene (2-methyl) butanone (18)
Reference to the synthesis of intermediate 6 gave 18 as a pale yellow solid in 91% yield,1H-NMR(300MHz,DMSO-d6)δ11.29(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 synthesis of example 1, the title compound was obtained from intermediate 18 and intermediate 8 as a brown solid in yield: 50%, mp 121-,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。
example 121- (3- (3-butanoyl-2, 6-dihydroxy-4-isopropoxy-5-methylbenzyl) -2,4, 6-trihydroxy-5-methylphenyl) -2-methylbutan-1-one
Figure BDA0001845508230000252
3-methyl-2-isopropoxy-4, 6-dimethoxymethoxybenzene (2-methyl) butanone (19)
The synthesis of reference intermediate 14 gave 19 as a colorless oil in yield: 81 percent of the total weight of the mixture,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-dihydroxybenzene (2-methyl) butanone (20)
The synthesis procedure referenced for intermediate 6 gave 20 as a white solid in yield: the content of the active ingredients is 92%,1H-NMR(400MHz,CDCl3)δ12.62(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 synthesis of example 1, the title compound was obtained from intermediate 20 and intermediate 7 as a yellow solid in yield: 44%, mp 65-66 deg.C,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。
example 131- (3- (3-butyryl-4- (chloropropoxy) -2, 6-dihydroxy-5-methylbenzyl) -2,4, 6-trihydroxy-5-methylphenyl) -2-methylbutan-1-one
Figure BDA0001845508230000253
2- (3-chloro) propoxy-3-methyl-4, 6-dimethoxymethoxybenzene (2-methyl) butanone (21)
The synthesis procedure referenced for intermediate 14 gave 21 as a colorless oil in yield: at a rate of 78%,1H-NMR(300MHz,DMSO-d6)δ6.68(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-chloro) propoxy-3-methyl-4, 6-dihydroxybenzene (2-methyl) butanone (22)
The synthesis procedure referenced for intermediate 6 gave 22 as a yellow solid in yield: 89 percent of the total weight of the mixture,1H-NMR(300MHz,DMSO-d6)δ11.88(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 synthesis of example 1, the title compound was obtained from intermediate 22 and intermediate 7 as a yellow oil in yield: the content of the raw materials is 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。
example 14N- (3- (2-butanoyl-3, 5-dihydroxy-6-methyl-4- (2,4, 6-trihydroxy-3-methyl-5- (2-methylbutanoyl) benzyl) phenoxy) propyl) acetamide
Figure BDA0001845508230000261
2- (3-amino) propoxy-3-methyl-4, 6-dimethoxymethoxybenzene (2-methyl) butanone (23)
The synthesis procedure referenced for intermediate 14 gave 23 as a colorless oil in yield: 67% of the total weight of the steel,1H-NMR(300MHz,Acetone-d6)δ5.97(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-amino) propoxy-3-methyl-4, 6-dihydroxybenzene (2-methyl) butanone (24)
The synthesis of reference intermediate 6 gave 24 as a pale yellow solid in yield: 81 percent of the total weight of the mixture,1H-NMR(300MHz,DMSO-d6)δ11.72(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) propoxy-3-methyl-4, 6-dihydroxybenzene (2-methyl) butanone (25)
The intermediate 24 reacts with acetic anhydride (1:1.2) to give the acetylated product 25 as a pale yellow solid, yield: 95 percent of the total weight of the mixture,1H-NMR(300MHz,DMSO-d6)δ12.03(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 synthesis of example 1, the title compound was obtained from intermediate 25 and intermediate 7 as a yellow solid in yield: 33 percent, mp 67-69 ℃,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)δ210.9,206.7,169.6,160.2,160.1,159.8,158.3,158.2,158.1,111.5,110.5,109.9,105.7,105.4,103.9,73.0,45.6,44.4,36.0,30.2,26.9,23.0,18.0,17.2,17.0,14.1,12.2,9.8,8.9.HRMS calcd for C29H40O9N[M+H]+:546.26976；found:546.27026。
example 151- (3- (3-butyryl-2, 6-dihydroxy-5-methyl-4- (2-propyn-1-oxy) benzyl) -2,4, 6-trihydroxy-5-methylphenyl) -2-methylbutan-1-one
Figure BDA0001845508230000262
2-propynyloxy-3-methyl-4, 6-dimethoxy methoxy benzene (2-methyl) butanone (26)
The synthesis of reference intermediate 14 gave colorless oil 26 in yield: the mass ratio of the raw materials is 66%,1H-NMR(300MHz,Acetone-d6)δ6.80(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-Propynyloxy-3-methyl-4, 6-dihydroxybenzene (2-methyl) butanone (27)
The synthesis procedure referenced for intermediate 6 gave 27 as a white solid in yield: the content of the active carbon is 83 percent,1H-NMR(300MHz,Acetone-d6)δ13.10(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 synthesis of example 1, the title compound was obtained from intermediate 27 and intermediate 7 as a light yellow solid in yield: 58 percent, mp 93-95 ℃,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。
example 161, 1' - (Methylenebis (2,4, 6-trihydroxy-3-methyl-5, 1-phenylene)) bis (butan-1-one)
Figure BDA0001845508230000271
Referring to the synthesis of example 1, the title compound was obtained from intermediate 3 as a light yellow solid in yield: 89%, mp 152-,1H-NMR(400MHz,CDCl3)δ15.50(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。
example 171- (3- (3-butanoyl-2, 6-dihydroxy-4-methoxy-5-methylbenzyl) -2, 4-dihydroxy-6-methoxy-5-methylphenyl) -2-methylbutan-1-one
Figure BDA0001845508230000272
Referring to the synthesis of example 1, the title compound was obtained from intermediate 6 and intermediate 18 as a yellow solid in yield: 44 percent, mp 97-99 ℃,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。
example 181- (3- (3-butanoyl-2, 4, 6-trihydroxy-5-methylbenzyl) -2, 4-dihydroxy-6-methoxy-5-methylphenyl) -2-methylbutan-1-one
Figure BDA0001845508230000273
Referring to the synthesis of example 1, the title compound was obtained from intermediate 3 and intermediate 18 as a yellow solid in yield: 44 percent, mp 81-83 ℃,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。
example 191, 1' - (Methylenebis (4, 6-dihydroxy-2-methoxy-3-methyl-5, 1-phenylene)) bis (2-methylbutan-1-one)
Figure BDA0001845508230000274
Referring to the synthesis of example 1, the title compound was obtained from intermediate 18 as a yellow solid in yield: 21%, mp 115-,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。
example 201, 1' - (Methylenebis (4, 6-dihydroxy-2-methoxy-3-methyl-5, 1-phenylene)) bis (butan-1-one)
Figure BDA0001845508230000275
Referring to the synthesis of example 1, the title compound was obtained from intermediate 6 as a yellow solid in yield: 89%, mp 137-,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。
example 211- (3- (3-butanoyl-2, 4, 6-trimethoxy-5-methylbenzyl) -2,4, 6-trimethoxy-5-methylphenyl) -2-methylbutan-1-one
Figure BDA0001845508230000281
The compound of example 1 (0.5mmol) was dissolved in 5mL acetone, potassium carbonate (3.0mmol) was added with stirring at room temperature, dimethyl sulfate (3.0mmol) was added for 2min, and after 5min refluxing for 3h, cooling, filtration, concentration of the filtrate under reduced pressure, silica gel column chromatography (petroleum ether/ethyl acetate ═ 30:1) gave the title compound as a light yellow oil, yield: 85 percent of the total weight of the mixture,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。
example 222- (2, 6-diacetoxy-3-butanoyl-4-methoxy-5-methylbenzyl) -4-methyl-6- (2-methylbutanoyl) benzene-1, 3, 5-triacetate
Figure BDA0001845508230000282
The compound of example 1 (0.5mmol) was dissolved in 5mL DCM, TEA (3.0mmol), acetic anhydride (3.0mmol) was added with stirring at room temperature, after stirring for 2h, concentrated under reduced pressure, and subjected to silica gel column chromatography (petroleum ether/ethyl acetate ═ 50:1) to give the title compound as a pale yellow solid in yield: 79%, mp 163-,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)δ204.5,203.4,168.7,168.1,167.9,167.8,167.8,154.9,149.8,149.5,145.3,144.5,143.7,127.5,126.7,124.3,123.6,123.4,121.5,62.7,48.4,45.9,25.2,21.8,20.6,20.5,20.4,17.1,15.1,13.8,11.6,10.8,9.9.HRMS calcd for C35H43O13[M+H]+:671.26982；found:671.26986。
example 231- (3- (3-butyryl-6-hydroxy-2, 4-dimethoxy-5-methylbenzyl) -2,4, 6-trihydroxy-5-methylphenyl) -2-methylbutan-1-one
Figure BDA0001845508230000283
2-methoxy-3-methyl-4-methoxymethoxy-6-hydroxy-phenylbutanone (28)
The synthesis procedure referenced for intermediate 4 gave intermediate 28 as a colorless oil in yield: the content of the active carbon is 83 percent,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-methoxy-phenyl butanone (29)
The synthesis procedure referenced for intermediate 5 gave intermediate 29 as a colorless oil in yield: 88 percent of the total weight of the mixture,1H-NMR(500MHz,Acetone-d6)δ6.64(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-hydroxy-phenylbutanone (30)
The synthesis procedure referenced for intermediate 6 gave intermediate 30 as a white solid in yield: 91 percent of the total weight of the mixture,1H-NMR(300MHz,Acetone-d6)δ8.57(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 synthesis of example 1, the title compound was obtained from intermediate 30 and intermediate 7 as a dark green solid in yield: 42%, mp 67-69 deg.C,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。
example 241- (3- (3-butanoyl-2, 6-dihydroxy-4-methoxy-5-methylbenzyl) -4-hydroxy-2, 6-dimethoxy-5-methylphenyl) -2-methylbutan-1-one
Figure BDA0001845508230000291
2-methoxy-3-methyl-4-methoxymethoxy-6-hydroxy-benzene (2-methyl) butanone (31)
The synthesis procedure referenced for intermediate 4 gave intermediate 31 as a colorless oil in yield: 77 percent of the total weight of the mixture,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-methoxymethyloxy-benzene (2-methyl) butanone (32)
The synthesis procedure referenced for intermediate 5 gave intermediate 32 as a colorless oil in yield: in the air of 84 percent,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-hydroxy-benzene (2-methyl) butanone (33)
The synthesis procedure referenced for intermediate 6 gave intermediate 33 as a white solid in yield: 89 percent of the total weight of the mixture,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- ((dimethylamino) methyl) -2, 4-dihydroxy-6-methoxy-5-methylbenzyl ethyl ketone (34)
To a solution of intermediate 6(0.5mmol) in DCM (3mL) was added N, N-tetramethylethylenediamine (0.6mmol) at rt, stirred for 2h, concentrated under reduced pressure, and chromatographed on silica gel (DCM/MeOH ═ 100:1) to give the title compound as a white solid in yield: the content of the active ingredients is 98 percent,1H-NMR(400MHz,CDCl3)δ3.77(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)。
to intermediate 33(0.1mmol), intermediate at room temperature34(0.12mmol) in 1, 4-dioxane (2mL) was added anhydrous zinc chloride (0.5mmol), refluxed for 8h, concentrated under reduced pressure, and subjected to silica gel column chromatography (petroleum ether/ethyl acetate ═ 40:1) to give the title compound as a pale yellow solid in yield: 36 percent, mp 69-71 ℃,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。
example 251- (3- (5-butyryl-2-hydroxy-4-methoxy-3-methylbenzyl) -2,4, 6-trihydroxy-5-methylphenyl) -2-methylbutan-1-one
Figure BDA0001845508230000292
2, 4-dihydroxy-3-methyl-phenyl butanone (35)
Referring to the synthesis of intermediate 3, starting from 2-methyl-1, 3-benzenediol, intermediate 35 was obtained as a white solid in yield: 75 percent of the total weight of the mixture,1H-NMR(400MHz,Acetone-d6)δ13.21(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-methoxy-2-hydroxy-3-methyl-phenyl-butanone (36)
The synthesis procedure referenced for intermediate 4 gave intermediate 36 as a colorless oil in yield: 87 percent of the total weight of the mixture,1H-NMR(400MHz,CDCl3)δ12.95(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-methoxy-2-methoxy-3-methyl-phenyl butanone (37)
The synthesis procedure referenced for intermediate 5 gave intermediate 37 as a white solid in yield: the content of the organic solvent is 90%,1H-NMR(400MHz,CDCl3)δ7.45(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-methoxy-4-hydroxy-3-methylbenzyl butanone (38)
The synthesis procedure referenced for intermediate 6 gave intermediate 38 as a white solid in yield: the content of the active ingredients is 92%,1H-NMR(400MHz,Acetone-d6)δ8.92(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 synthesis of example 1, the title compound was obtained from intermediate 38 and intermediate 7 as a light yellow solid in yield: 32%, mp109-111 ℃,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。
example 261- (5- (3-butanoyl-2, 6-dihydroxy-4-methoxy-5-methylbenzyl) -2, 4-dihydroxy-3-methylphenyl) -2-methylbutan-1-one
Figure BDA0001845508230000301
2, 4-dihydroxy-3-methyl-benzene (2-methyl) butanone (39)
Referring to the synthesis of intermediate 3, starting from 2-methyl-1, 3-benzenediol, intermediate 39 was obtained as a white solid in yield: at a rate of 78%,1H-NMR(400MHz,CDCl3)δ13.42(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 synthesis of example 1, the title compound was obtained from intermediate 38 and intermediate 7 as a yellow solid in yield: 34%, mp 105-,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。
example 271- (3- (3-butanoyl-2, 6-dihydroxy-4-methoxy-5-methylbenzyl) -4, 6-dihydroxy-2, 5-dimethoxyphenyl) -2-methylbutan-1-one
Figure BDA0001845508230000302
2, 4-dihydroxy-3, 6-dimethyl-benzene (2-methyl) butanone (40)
Referring to the synthesis of intermediate 3, starting from 2, 5-dimethyl-1, 3-benzenediol, intermediate 40 was obtained as a brown solid in yield: in the air of 84 percent,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 synthesis of example 1, the title compound was obtained from intermediate 38 and intermediate 7 as a red solid in yield: 38 percent, mp 59-61 ℃,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。
example 281- (3- (3-butanoyl-2, 6-dihydroxy-4-methoxy-5-methylbenzyl) -2-hydroxy-4, 6-dimethoxy-5-methylphenyl) butan-1-one
Figure BDA0001845508230000303
Referring to the synthesis of example 21, the title compound was obtained from the title compound of example 20 as light yellow solid in yield: 45%, mp 108-,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。
example 291- (3- (3-butyryl-2-hydroxy-4, 6-dimethoxy-5-methylbenzyl) -4-hydroxy-2, 6-dimethoxy-5-methylphenyl) butan-1-one
Figure BDA0001845508230000304
Referring to the synthesis of example 21, the title compound was obtained from the title compound of example 20 as light yellow solid in yield: 35 percent, mp 90-92 ℃,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。
example 301- (3- (3-butanoyl-2, 4, 6-trimethoxy-5-methylbenzyl) -2-hydroxy-4, 6-dimethoxy-5-methylphenyl) butan-1-one
Figure BDA0001845508230000311
Referring to the synthesis of example 21, the title compound was obtained from the title compound of example 20 as light yellow solid in yield: 41 percent, mp 75-77 ℃,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。
example 311, 1' - (Methylenebis (2,4, 6-trimethoxy-3-methyl-5, 1-phenylene)) bis (butan-1-one)
Figure BDA0001845508230000312
Referring to the synthesis of example 21, the title compound was obtained from the title compound of example 20 as light yellow oil in yield: 88 percent of the total weight of the mixture,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。
example 324-butyryl-2- (3-butyryl-2, 6-dihydroxy-4-methoxy-5-methylbenzyl) -3-hydroxy-5-methoxy-6-methylphenyl acetate
Figure BDA0001845508230000313
Referring to the synthesis of example 22, the title compound was obtained from the title compound of example 20 as light yellow solid in yield: 40%, mp 122-,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。
example 332- (2-acetoxy-5-butanoyl-6-hydroxy-4-methoxy-3-methylbenzyl) -4-butanoyl-5-methoxy-6-methyl-1, 3-phenylenediacetic acid ester
Figure BDA0001845508230000314
Referring to the synthesis of example 22, the title compound was obtained from the title compound of example 20 as light yellow solid in yield: 43 percent, mp 46-48 ℃,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。
example 342- (2, 6-diacetoxy-5-butyryl-6-hydroxy-4-methoxy-3-methylbenzyl) -4-butyryl-5-methoxy-6-methyl-1, 3-phenylenediacetic acid ester
Figure BDA0001845508230000315
Referring to the synthesis of example 22, the title compound was obtained from the title compound of example 20 as light yellow solid in yield: 79%, mp 105-,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。
example 351- (3- (3-butanoyl-2, 6-dihydroxy-4-methoxy-5-methylbenzyl) -2, 4-dihydroxy-5-methyl-6- (2-propyn-1-oxy) phenyl) butan-1-one
Figure BDA0001845508230000321
Referring to the synthesis of example 1, the title compound was obtained from intermediate 6 and intermediate 27 as a light yellow solid in yield: 41 percent, mp98-100 ℃,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。
example 361' 1- (methylenebis (4, 6-dihydroxy-3-methyl-2- (2-propyn-1-oxy) -5, 1-phenylene)) bis (butan-1-one)
Figure BDA0001845508230000322
Referring to the synthesis of example 1, the title compound was obtained from intermediate 27 as a light yellow solid in yield: 41%, mp 184-,1H-NMR(300MHz,CDCl3)δ15.40(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。
example 371- (3- (3-butanoyl-2, 6-dihydroxy-4-methoxy-5-methylbenzyl) -2,4, 6-trihydroxyphenyl) -2-methylbutan-1-one
Figure BDA0001845508230000323
Referring to the synthesis of intermediate 3, starting with phloroglucinol, intermediate 41 was obtained as a dark yellow oil in yield: 76 percent of the total weight of the mixture,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 synthesis of example 1, the title compound was obtained from intermediate 6 and intermediate 41 as a brown solid in yield: 41 percent, mp 96-98 ℃,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。
example 381- (3- (3-butanoyl-2, 6-dihydroxy-4-methoxybenzyl) -2,4, 6-trihydroxy-5-methylphenyl) -2-methylbutan-1-one
Figure BDA0001845508230000324
2,4, 6-trihydroxy benzene butanone (42)
Referring to the synthesis of intermediate 3, starting with phloroglucinol, intermediate 42 was obtained as a yellow oil in yield: 81 percent of the total weight of the mixture,1H-NMR(400MHz,Acetone-d6)δ11.69(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-Dimethoxymethoxy-6-hydroxybenzenebutanone (43)
The synthesis procedure referenced for intermediate 4 gave intermediate 43 as a colorless oil in yield: 88 percent of the total weight of the mixture,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-Dimethoxymethoxy-6-methoxybenzyl butanone (44)
The synthesis procedure referenced for intermediate 5 gave intermediate 44 as a colorless oil in yield: 79 percent of the total weight of the mixture,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-methoxy-4, 6-dihydroxy-benzene butanone (45)
The synthesis procedure referenced for intermediate 6 gave intermediate 45 as a yellow solid in yield: 91 percent of the total weight of the mixture,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 synthesis of example 1, the title compound was obtained from intermediate 7 and intermediate 45 as a yellow solid in yield: 52%, mp 147-,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。
example 391, 1' - (Methylenebis (2, 4-dihydroxy-6-methoxy-3, 1-phenylene)) bis (butan-1-one)
Figure BDA0001845508230000331
Referring to the synthesis of example 1, the title compound was obtained from intermediate 45 as a yellow solid in yield: 28%, mp 205-,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。
example 401- (3- (1- (3-butanoyl 2, 6-dihydroxy-4-methoxy-5-methylphenyl) ethyl) -2,4, 6-trihydroxy-5-methylphenyl) -2-methylbutan-1-one
Figure BDA0001845508230000332
Dissolving intermediate 6(0.1mmol) and intermediate 7(0.1mmol) in 3mL DCM, adding TsCl (0.1mmol), 10 drops of aqueous acetaldehyde solution, 1 spoon of anhydrous sodium sulfate, refluxing for 8h, filtering, concentrating under reduced pressure, and filtering18Silica gel column chromatography (MeOH/H)2O95: 5) gave the title compound as a yellow solid in yield: 20 percent, mp 88-90 ℃,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。
example 411- (3- ((3-butyryl-2, 6-dihydroxy-4-methoxy-5-methylphenyl) (phenyl) methyl) -2,4, 6-trihydroxy-5-methylphenyl) -2-methylbutan-1-one
Figure BDA0001845508230000333
Intermediate 6(0.1mmol) and intermediate 7(0.1mmol) were dissolved in 3mL DCM, TsCl (0.1mmol) and benzaldehyde (1mmol) were added, and after refluxing for 8h, filtration and concentration under reduced pressure were carried out to obtain solution C18Silica gel column chromatography (MeOH/H)2O95: 5) gave the title compound as a yellow solid in yield: 29 percent, mp 95-97 ℃,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。
example 422-methyl-4- (2,4, 6-trihydroxybenzyl) benzene-1, 3, 5-trisphenol
Figure BDA0001845508230000334
The synthesis of reference intermediate 2 gave the title compound as a yellow solid in yield: 45%, mp 132-,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)δ158.0,156.3,155.5,155.3,152.9,106.7,106.6,104.4,96.4,95.8,17.4,8.6.HRMS calcd for C14H15O6[M+H]+:279.08631；found:279.08612。
example 438- (3-butanoyl-2, 6-dihydroxy-4-methoxy-5-methylphenyl) -2-ethyl-5, 7-dihydroxy-2, 6-dimethylchroman-4-one
Figure BDA0001845508230000335
3-methyl-2-pentenoic acid ethyl ester (46)
To a solution of NaH (50mmo) in THF (50mL) at 0 deg.C was added dropwise triethyl phosphonoacetate (50mmol) and stirred for 1h, followed by slow dropwise addition of 2-butanone (50mmol) and stirring at room temperature for 3h, addition of saturated NH4The reaction was quenched with Cl solution, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give intermediate 46 as a pale yellow oil. The crude product was used directly in the next reaction.
3-methyl-2-pentenoic acid (47)
To intermediate 46 in methanol (30mL) was addedAdding 2N KOH solution (30mL,60mmol), refluxing for 20hs, concentrating under reduced pressure to 1/5 volume, cooling to 0 deg.C, adjusting pH to 2 with 1N diluted hydrochloric acid, extracting with ethyl acetate, washing with saturated saline, drying with anhydrous sodium sulfate, filtering, concentrating under reduced pressure, performing silica gel column chromatography (PE/EA is 5:1) to obtain intermediate 47 as yellow oil with yield of 42.1% in two steps,1H-NMR(400MHz,Acetone-d6)：(E/Z＝2.7:1).E isomerδ5.67(s,1H),2.18(q,J＝7.6,2H),2.14(s,3H),1.06(t,J＝7.6,3H)；Zisomerδ5.65(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-one (48a) and 2-Ethyl-5, 7-dihydroxy-2, 8-dimethylchroman-4-one (48 a')
Adding 10mL of boron trifluoride diethyl etherate into a mixture of the intermediate 2(4mmol) and 47(4.4mmol) at room temperature, heating the mixed solution to 70 ℃, reacting for 2h, cooling, pouring into ice water, extracting with ethyl acetate, drying with anhydrous sodium sulfate, concentrating under reduced pressure, performing silica gel column chromatography (PE/DCM ═ 5:1) to obtain 48a as a yellow solid with the yield of 52%,1H-NMR(300MHz,DMSO-d6) δ 12.34(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 48 a', a pale yellow solid, yield 25%,1H-NMR(300MHz,DMSO-d6)δ12.02(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 synthesis of example 40, the title compound was obtained from intermediate 6 and intermediate 48a as a pale yellow solid in 17.5% yield, 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]+。
example 448, 8' -methylenebis (2-ethyl-5, 7-dihydroxy-2, 6-dimethylchroman-4-one)
Figure BDA0001845508230000341
Referring to the synthesis of example 40, the title compound was obtained as intermediate 48a in 25.1% yield as a light yellow solid, mp:195-,197 ℃,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]+。
example 456- (3-butanoyl-2, 6-dihydroxy-4-methoxy-5-methylphenyl) -2-ethyl-5, 7-dihydroxy-2, 8-dimethylchroman-4-one
Figure BDA0001845508230000342
Referring to the synthesis of example 40, the title compound was obtained from intermediate 6 and intermediate 48 a' in the form of a light yellow solid with a yield of 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]+。
example 466, 6' -methylenebis (2-ethyl-5, 7-dihydroxy-2, 8-dimethylchroman-4-one)
Figure BDA0001845508230000343
Referring to the synthesis of example 40, the title compound was obtained from intermediate 48 a' in 39.9% yield as yellow solid, mp 213-,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]+。
example 478- (3-butyryl-2, 6-dihydroxy-4-methoxy-5-methylphenyl) -6-chloro-2-ethyl-5, 7-dihydroxy-2-methylchroman-4-one
Figure BDA0001845508230000351
3-chloro-2, 4, 6-trihydroxybenzoic acid (49)
SO was added dropwise to a solution of 2,4, 6-trihydroxybenzoic acid monohydrate (20mmol) in anhydrous ether (50mL) at 0 deg.C2Cl2(24mmol), stirring at room temperature for 2h after the dropwise addition, pouring the reaction solution into ice water, drying with anhydrous sodium sulfate, concentrating under reduced pressure to obtain intermediate 49 which is a light yellow solid with the yield of 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-Trihydroxyl Chlorobenzene (50)
Dissolving intermediate 49(10mmol) in 18mLN, N-dimethylaniline, reacting at 150 deg.C for 2h, cooling, pouring the reaction solution into ice water solution of concentrated hydrochloric acid, extracting with ethyl acetate, washing with 6N hydrochloric acid solution, drying with anhydrous sodium sulfate, concentrating under reduced pressure, performing silica gel column chromatography (DCM/Methanol ═ 80:1) to obtain intermediate 50, which is light yellow solid with yield of 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]-。
6-chloro-2-ethyl-5, 7-dihydroxy-2-methylchroman-4-one (51a) and 8-chloro-2-ethyl-5, 7-dihydroxy-2-methylchroman-4-one (51 a')
Reference to the synthesis of intermediate 48 gave intermediate 51a as a pale yellow solid in 55% yield,1H-NMR(300MHz,DMSO-d6)δ12.66(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]+(ii) a And 51 a', yellow solid, yield 17%,1H-NMR(400MHz,DMSO-d6)δ12.02(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 synthesis of example 24, the title compound was obtained from intermediate 34 and intermediate 51a as a pale yellow solid in 21.8% yield, mp:116 and 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]+。
example 486- (3-butyryl-2, 6-dihydroxy-4-methoxy-5-methylphenyl) -8-chloro-2-ethyl-5, 7-dihydroxy-2-methylchroman-4-one
Figure BDA0001845508230000352
Referring to the synthesis of example 24, the title compound was obtained from intermediate 34 and intermediate 51 a' as a yellow oil in 36.5% yield,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]+。
example 498- (3-butyryl-2, 6-dihydroxy-4-methoxy-5-methylphenyl) -6-bromo-2-ethyl-5, 7-dihydroxy-2-methylchroman-4-one
Figure BDA0001845508230000361
2,4, 6-Trihydroxyl bromobenzene (52) and 2,4, 6-Trihydroxyl-1, 3-Dibromobenzene (53)
Adding ammonium bromide (22mmol) and potassium hydrogen peroxymonosulfate complex salt (22mmol) into phloroglucinol (20mmol) in methanol (100mL) at room temperature, reacting for 30min, filtering, concentrating under reduced pressure, performing silica gel column chromatography (DCM/methanol ═ 50:1) to obtain intermediate 52 as a white solid with a yield of 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]-(ii) a And intermediate 53, a yellow solid, yield 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]-。
6-bromo-2-ethyl-5, 7-dihydroxy-2-methylchroman-4-one (54a) and 8-bromo-2-ethyl-5, 7-dihydroxy-2-methylchroman-4-one (54 a')
Reference to the synthesis of intermediate 48 gave intermediate 54a as a yellow solid in 48% yield,1H-NMR(400MHz,DMSO-d6)δ12.80(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]-(ii) a And 54 a', yellow solid, yield 19%,1H-NMR(400MHz,DMSO-d6)δ12.07(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 synthesis of example 24, the title compound was obtained from intermediate 34 and intermediate 54a as a yellow solid in 24.2% yield, mp:108-,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]+。
example 506- (3-butyryl-2, 6-dihydroxy-4-methoxy-5-methylphenyl) -8-bromo-2-ethyl-5, 7-dihydroxy-2-methylchroman-4-one
Figure BDA0001845508230000362
Referring to the synthesis of example 24, the title compound was obtained from intermediate 34 and intermediate 54 a' as a yellow oil in 18.7% yield,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]+.
example 518- (3-butyryl-2, 6-dihydroxy-4-methoxy-5-methylphenyl) -6-carboxylic acid methyl ester-2-ethyl-5, 7-dihydroxy-2-methylchroman-4-one
Figure BDA0001845508230000363
2,4, 6-Trihydroxybenzoic acid methyl ester (55)
To 2,4, 6-trihydroxybenzoic acid monohydrate (20mmol) and K at room temperature2CO3(20mmol) in acetone (50mL) was added dimethyl sulfate (22mmol), stirred for 48h, filtered, concentrated under reduced pressure, the solid dissolved in ethyl acetate and diluted with 5% hydrochloric acid, saturated NaHCO3The solution and saturated brine were successively washed, the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and subjected to silica gel column chromatography (DCM/MeOH ═ 25:1) as intermediate 55 in the form of yellow solid with a yield of 97.7%,1H-NMR(300MHz,DMSO-d6)δ10.38(s,2H),10.16(s,1H),5.80(s,1H),3.80(s,1H)；ESI-MS:calculated,184.15；found,182.92[M-H]-。
methyl 6-carboxylate-2-ethyl-5, 7-dihydroxy-2-methylchroman-4-one (56a) and methyl 8-carboxylate-2-ethyl-5, 7-dihydroxy-2-methylchroman-4-one (56 a')
Reference to the synthesis of intermediate 48 gave intermediate 56a as a white solid in 39% yield,1H-NMR(300MHz,DMSO-d6)δ12.94(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]+(ii) a And intermediate 56 a', yellow solid, yield 32%,1H-NMR(300MHz,DMSO-d6)δ12.26(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 synthesis of example 24, the title compound was obtained from intermediate 34 and intermediate 56a as a yellow solid in 22.8% yield, mp:154-156 ℃;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]+。
example 526- (3-butanoyl-2, 6-dihydroxy-4-methoxy-5-methylphenyl) -8-carboxylic acid methyl ester-2-ethyl-5, 7-dihydroxy-2-methylchroman-4-one
Figure BDA0001845508230000371
Referring to the synthesis of example 24, the title compound was obtained from intermediate 34 and intermediate 56 a' as a yellow solid in 44 yield.5％，mp:130-132℃，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]+。
Example 536, 6' -Methylenebis (2-ethyl-5, 7-dihydroxy-2, 8-dicarboxylic acid methyl ester chroman-4-one)
Figure BDA0001845508230000372
Referring to the synthesis of example 24, the title compound was obtained from intermediate 56 a' in 14.7% yield as a yellow solid, mp:212-,214 ℃,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]+。
example 548- (3-butanoyl-2, 6-dihydroxy-4-methoxy-5-methylphenyl) -6-chloro-2, 2-diethyl-5, 7-dihydroxy-chroman-4-one
Figure BDA0001845508230000373
3-Ethyl-2-pentenoic acid (57)
Reference to the synthesis of intermediate 47 gave intermediate 57 in 52.7% yield,1H-NMR(300MHz,Acetone-d6)δ5.62(s,1H),2.63(q,J＝7.5Hz,2H),2.22(m,2H),1.05(m,6H).
6-chloro-2, 2-diethyl-5, 7-dihydroxy chroman-4-one (58a) and 8-chloro-2, 2-diethyl-5, 7-dihydroxy chroman-4-one (58 a')
Reference to the synthesis of intermediate 48 gave intermediate 58a as a yellow solid in 32% yield,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]-(ii) a And 58 a', 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 synthesis of example 24, the title compound was obtained from intermediate 34 and intermediate 58a as a yellow solid in 23.7% yield, mp:155-,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]+。
example 556- (3-butyryl-2, 6-dihydroxy-4-methoxy-5-methylphenyl) -8-chloro-2, 2-diethyl-5, 7-dihydroxychroman-4-one
Figure BDA0001845508230000374
With reference to the synthesis of example 24, the title compound was obtained from intermediate 34 and intermediate 58aBy yellow solid, yield 25.0%, mp 115-;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]+。
example 568- (3-butyryl-2, 6-dihydroxy-4-methoxy-5-methylphenyl) -6-chloro-2, 2-dimethyl-5, 7-dihydroxychroman-4-one
Figure BDA0001845508230000381
6-chloro-2, 2-dimethyl-5, 7-dihydroxy chroman-4-one (59a) and 8-chloro-2, 2-dimethyl-5, 7-dihydroxy chroman-4-one (59 a')
Reference to the synthesis of intermediate 48 gave intermediate 59a as a yellow solid in 54% yield,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]-(ii) a And 59 a', 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 synthesis of example 24, the title compound was obtained as a yellow solid from intermediate 34 and intermediate 59a in 19.3% yield, mp: 193-;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]+。
example 576- (3-butyryl-2, 6-dihydroxy-4-methoxy-5-methylphenyl) -8-chloro-2, 2-dimethyl-5, 7-dihydroxychroman-4-one
Figure BDA0001845508230000382
Referring to the synthesis of example 24, the title compound was obtained as a yellow solid from intermediate 34 and intermediate 59 a', yield 33.4%, mp:191-193 ℃;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]+。
example 588- (3-butyryl-2, 6-dihydroxy-4-methoxy-5-methylphenyl) -6-chloro-2-propyl-5, 7-dihydroxy-2-methylchroman-4-one
Figure BDA0001845508230000383
3-methyl-2-hexenoic acid (60)
Reference to the synthesis of intermediate 47 gave intermediate 60 in 72.8% yield,1H-NMR(400MHz,Acetone-d6)(E/Z＝3:2).E isomerδ10.32(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 isomerδ10.32(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]-。
6-chloro-2-propyl-5, 7-dihydroxy-2-methylchroman-4-one (61a) and 8-chloro-2-propyl-5, 7-dihydroxy-2-methylchroman-4-one (61 a')
Reference to the synthesis of intermediate 48 gave intermediate 61a as a yellow solid in 34% yield,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 61 a', yellow solid, yield 27%,1H-NMR(400MHz,CDCl3)δ11.92(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 synthesis of example 24, the title compound was obtained from intermediate 34 and intermediate 61a as a yellow solid in 11.4% yield, mp:157-,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]+。
example 596- (3-butyryl-2, 6-dihydroxy-4-methoxy-5-methylphenyl) -8-chloro-2-propyl-5, 7-dihydroxy-2-methylchroman-4-one
Figure BDA0001845508230000391
Referring to the synthesis of example 24, the title compound was obtained from intermediate 34 and intermediate 61 a' as a yellow oil in 14.8% yield,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]+。
example 606-chloro-8- (2, 6-dihydroxy-4-methoxy-3-methyl-5- (2-methylbutyryl) phenyl) -2-ethyl-5, 7-dihydroxy-2-methylchroman-4-one
Figure BDA0001845508230000392
Referring to the synthesis of example 24, the title compound was obtained as a yellow solid from intermediate 18 and intermediate 51a in 12.4% yield, mp: 157-;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]+。
example 616-chloro-8- (2, 6-dihydroxy-4-methoxy-3-methyl-5- (2-methylbutyryl) phenyl) -5, 7-dihydroxy-2-methyl-2-propylchroman-4-one
Figure BDA0001845508230000393
Referring to the synthesis of example 24, the title compound was obtained from intermediate 18 and intermediate 61a as a yellow solid in 12.7% yield, mp: 114-;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]+。
example 628- (3-butyryl-2, 6-dihydroxy-4-methoxy-5-methylphenyl) -6-chloro-3-ethyl-5, 7-dihydroxy-chroman-4-one
Figure BDA0001845508230000394
2,4, 6-trihydroxy-3-chlorobenzene butanone (62)
Reference to the synthesis of intermediate 3 gave intermediate 62 as a yellow solid in 58% yield,1H-NMR(400MHz,Acetone-d6)δ13.52(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)。
6-hydroxy-3-chloro-2, 4-dimethoxymethoxybenzene butanone (63)
The synthesis of intermediate 4 gave intermediate 63 as a yellow oil in 46% yield,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)。
6-chloro-3-ethyl-5, 7-dimethoxy methoxy chroman-4-one (64)
In a 50mL round-bottom flask, the starting material was added63(1.3553mmol), dissolving in 25mL of absolute ethyl alcohol, adding paraformaldehyde (4.7435mmol) and diethylamine (13.553mmol), heating and refluxing the reaction solution for 24h, concentrating under reduced pressure, dissolving in ethyl acetate, washing with water, drying with anhydrous sodium sulfate, concentrating, performing silica gel column chromatography (PE/EA 15:1) to obtain 64 as yellow oily substance with yield of 74%,1H-NMR(400MHz,Acetone-d6)δ6.60(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)。
6-chloro-3-ethyl-5, 7-dihydroxy chroman-4-one (65)
Reference to the synthesis of intermediate 6 gave intermediate 65 as a yellow solid in 63% yield,1H-NMR(400MHz,Acetone-d6)δ12.86(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 synthesis of example 24, the title compound was obtained from intermediate 34 and intermediate 65 as a yellow solid in 19.8% yield, mp: 147-;1H-NMR(400MHz,Acetone-d6)δ12.86(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]+。
example 638- (3-butanoyl-2, 6-dihydroxy-4-methoxy-5-methylphenyl) -6-chloro-3-methyl-5, 7-dihydroxy-chroman-4-one
Figure BDA0001845508230000401
2,4, 6-Trihydroxyl-3-Chlorobenzenepropanone (66)
Reference to the synthesis of intermediate 3 gave intermediate 66 as a grey solid in 73% yield,1H-NMR(400MHz,DMSO-d6)δ14.31(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)。
6-hydroxy-3-chloro-2, 4-dimethoxy methoxy propiophenone (67)
Reference to the synthesis of intermediate 4 gave intermediate 67 as a yellow solid in 43.2% yield,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)。
6-chloro-3-methyl-5, 7-dimethoxy methoxy chroman-4-one (68)
Reference synthesis of intermediate 64 gave intermediate 68 as a yellow oil in 79% yield,1H-NMR(400MHz,Acetone-d6)δ6.61(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)。
6-chloro-3-methyl-5, 7-dihydroxy chroman-4-one (69)
Reference to the synthesis of intermediate 6 gave intermediate 69 as a yellow solid in 71.4% yield,1H-NMR(400MHz,Acetone-d6)δ12.84(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 synthesis of example 24, the title compound was obtained from intermediate 34 and intermediate 69 as a yellow solid in 22.4% yield mp:169-,171 ℃,1H-NMR(400MHz,Acetone-d6)δ13.11(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]+。
example 648- (3-butyl-2, 6-dihydroxy-4-methoxy-5-methylphenyl) -6-chloro-2-ethyl-5, 7-dihydroxy-2-methylchroman-4-one
Figure BDA0001845508230000402
4-butyl-5-methoxy-6-methylphenyl-1, 3-diol (70)
Adding raw material 6(0.8mmol) and Zn powder (8mmol) into a 25mL round-bottom flask, dissolving in 5mL methanol, cooling to 0 ℃, carefully dropwise adding concentrated hydrochloric acid 1.2mL, after dropwise addition, raising the temperature of the reaction solution to room temperature for reaction for 2.5h, diluting the reaction solution with saturated saline solution, extracting with ethyl acetate, combining organic phases, washing with saturated saline solution, drying with anhydrous sodium sulfate, concentrating, performing silica gel column chromatography (PE/EA is 10:1) to obtain an intermediate 70, obtaining a yellow oily substance with the yield of 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 synthesis of example 24, the title compound was obtained from intermediate 70 and intermediate 51a as a yellow solid in 11.7% yield, mp: 127-;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]+。
example 651- (3- ((6-chloro-2-ethyl-5, 7-dihydroxy-2-methylchroman-8-yl) methyl) -2, 4-dihydroxy-6-methoxy-5-methylphenyl) butane
Figure BDA0001845508230000411
6-chloro-2-ethyl-2-methyl chroman-5, 7-diol (71)
Reference to the synthesis of intermediate 70 gave intermediate 71 as a yellow solid in 60.4% yield,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 synthesis of example 24, the title compound was obtained from intermediate 70 and intermediate 71 as a yellow solid in 18.0% yield,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]+。
example 668- (3-butyl-2, 6-dihydroxy-4-methoxy-5-methylphenyl) -6-chloro-5, 7-dihydroxy-3-methylchroman-4-one
Figure BDA0001845508230000412
Referring to the synthesis of example 24, the title compound was obtained from intermediate 69 and intermediate 70 as a yellow solid in 11.3% yield,1H-NMR(400MHz,Acetone-d6)δ13.20(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]+。
example 678- (3-butanoyl-2, 6-dihydroxy-4-methoxy-5-methylphenyl) -6-chloro-2-ethyl-7-hydroxy-5-methoxy-2-methylchroman-4-one
Figure BDA0001845508230000413
6-chloro-7- (4-methylbenzenesulfonic acid) -5-methoxy-2-ethyl-2-methylchroman-4-one (72)
In a 50mL round-bottom flask, the starting materials 51a (0.4mmol), K were added sequentially2CO3(2.8mmol) and TsCl (0.4mmol), 25mL acetone, the corresponding yellow solution was heated under reflux for 5h, cooled, and K was added2CO3(1.2mmol) and Me2SO4(0.44mmol), reflux-heating for 20h, cooling, filtering, concentrating under reduced pressure, silica gel column chromatography (PE/EA 60:1) to give intermediate 72 as a yellow oil in 74% yield,1H-NMR(400MHz,Acetone-d6)δ7.85(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-methoxy-7-hydroxy-2-ethyl-2-methyl chroman-4-one (73)
To a solution of intermediate 72(0.296mmol) in tetrahydrofuran (5mL) was added tetrabutylammonium fluoride trihydrate (0.888mmol) at room temperature, stirred for 3h, concentrated under reduced pressure, the residue dissolved in 50mL ethyl acetate, washed with 25mL water, dried over anhydrous sodium sulfate, and the silica gel column layerIntermediate 73 was isolated as a pale yellow solid in 62% yield,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 synthesis of example 24, the title compound was obtained from intermediate 34 and intermediate 73 as a yellow solid in 11.6% yield, mp:201-,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]+。
example 686-chloro-2-ethyl-8- ((3-ethyl-5, 7-dihydroxy-8-methyl-4-chroman-6-yl) methyl) 5, 7-dihydroxy-2-methyl chroman-4-one
Figure BDA0001845508230000414
3-Ethyl-5, 7-dimethoxymethoxy-8-methylchroman-4-one (74)
Reference to the synthesis of intermediate 64 gave intermediate 74 as a yellow oil in 82% yield,1H-NMR(400MHz,Acetone-d6)δ6.55(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-methylchroman-4-one (75)
Reference to the synthesis of intermediate 6 gave intermediate 75 as a white solid in 65% yield,1H-NMR(400MHz,Acetone-d6)δ12.20(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- ((dimethylamino) methyl) -3-ethyl-5, 7-dihydroxy-8-methylchroman-4-one (76)
The synthesis procedure referred to intermediate 34 gave intermediate 76 as a yellow solid in 87% yield,1H-NMR(400MHz,Acetone-d6)δ12.70(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 synthesis of example 24, the title compound was obtained as a yellow solid from intermediate 51a and intermediate 76 in 15.1% yield mp:187-189 ℃;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]+。
example 696-bromo-2-ethyl-8- ((3-ethyl-5, 7-dihydroxy-8-methyl-4-chroman-6-yl) methyl) 5, 7-dihydroxy-2-methylchroman-4-one
Figure BDA0001845508230000421
Referring to the synthesis of example 24, the title compound was obtained from intermediate 54a and intermediate 76 as a yellow solid in 14.6% yield, mp:192-,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]+。
example 706-chloro-8- ((3-ethyl-5, 7-dihydroxy-8-methyl-4-chroman-6-yl) methyl) -5, 7-dihydroxy-3-methylchroman-4-one
Figure BDA0001845508230000422
Referring to the synthesis of example 24, the title compound was obtained from intermediate 69 and intermediate 76 as a yellow solid 13.4mg in 11.6% yield, mp: 196-;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]+。
example 716-chloro-8- ((3-ethyl-5, 7-dihydroxy-8-methyl-4-chroman-6-yl) methyl) -5, 7-dihydroxy-2, 2-dimethylchroman-4-one
Figure BDA0001845508230000423
Referring to the synthesis of example 24, the title compound was obtained as a yellow solid from intermediate 76 and intermediate 59a in 8.6% yield, mp:214-216 ℃;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]+。
example 726-chloro-2-ethyl-8- ((3-ethyl-7-hydroxy-5-methoxy-6-methyl-4-chroman-8-yl) methyl) -5, 7-dihydroxy-2-methylchroman-4-one
Figure BDA0001845508230000431
4-Methoxymethyloxy-2-methoxy-6-hydroxy-3-methylbenzyl butanone (77)
Reference to the synthesis of intermediate 4 gave intermediate 77 as a yellow oil in 69.8% yield,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-methoxy-7- (methoxymethyloxy) -6-methylchroman-4-one (78)
Reference to the synthesis of intermediate 64 gave intermediate 78 as a yellow oil in 92% yield,1H-NMR(400MHz,Acetone-d6)δ6.44(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-methoxy-7-hydroxy-6-methyl chroman-4-one (79)
Reference to the synthesis of intermediate 6 gave intermediate 79 as a white solid in 77.6% yield,1H-NMR(400MHz,Acetone-d6)δ9.27(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- ((dimethylamino) methyl) -3-ethyl-5-methoxy-7-hydroxy-6-methylchroman-4-one (80)
Reference to the synthesis of intermediate 34 gave intermediate 80 as a yellow solid in 92.6% yield,1H-NMR(400MHz,Acetone-d6)δ4.50(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 synthesis of example 24, the title compound was obtained from intermediate 80 and intermediate 59a as a yellow oil in 22.9% yield,1H-NMR(400MHz,Acetone-d6)δ12.72(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]+。
example 736-chloro-2-ethyl-5, 7-dihydroxy-8- ((6-hydroxy-4-methoxy-5-methyl-3-propylbenzo [ d ] isoxazol-7-yl) methyl) -2-methylchroman-4-one
Figure BDA0001845508230000432
6-hydroxy-4-methoxy-5-methyl-3-propylbenzo [ d ] isoxazole (81)
6(2.5mmol), hydroxylamine hydrochloride (5mmol) and sodium acetate (5mmol) are added into a 100mL round bottom flask, dissolved in 15mL ethanol and 5mL water, refluxed for 16h, concentrated under reduced pressure, added with proper amount of water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, concentrated to obtain a crude product, and directly put into the next reaction. To a 50mL round bottom flask, PPh was added3(3mmol) and DDQ (3mmol) in 10mL dry DCM, after stirring at room temperature for 5min, the crude oxime was added, stirred at room temperature for 30min, concentrated under reduced pressure, and chromatographed on silica gel (PE/EA: 40:1) to give 81 as a white solid in 31% yield,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- ((dimethylamino) methyl) -6-hydroxy-4-methoxy-5-methyl-3-propylbenzo [ d ] isoxazole (82)
Reference to the synthesis of intermediate 34 gave intermediate 82 as a yellow oil in 85% yield,1H-NMR(400MHz,Acetone-d6)δ4.26(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 synthesis of example 24, the title compound was obtained as a yellow solid from intermediate 82 and intermediate 59a in 13.3% yield, mp:166-168 ℃;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]+。
example 747, 7' -methylenebis (4-methoxy-5-methyl-3-propylbenzo [ d ] isoxazol-6-ol)
Figure BDA0001845508230000433
Referring to the synthesis of example 24, the title compound was obtained as intermediate 82 in 16.2% yield as a yellow solid in mp: 192-;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]+。
example 756- (3-chloro-2, 4, 6-trihydroxy-5- (2-methylbutyryl) phenyl) -3-ethyl-5, 7-dihydroxy-8-methylchroman-4-one
Figure BDA0001845508230000441
1- (3-chloro-2, 4, 6-trihydroxyphenyl) -2-methylbutane-1-one (83)
Adding raw material 50(3.5mmol) and boron trifluoride diethyl etherate (19.25mmol) into a 50mL round-bottom flask, dissolving in 15mL 1, 2-dichloroethane, stirring for 2min, adding 2-methylbutyryl chloride (3.85mmol), refluxing for 3h, concentrating under reduced pressure, extracting the residue with EA and 3M HCl solution, stirring for 10min, washing the organic phase with saturated common salt water, drying over anhydrous sodium sulfate, concentrating, performing silica gel column chromatography (PE/EA is 5:1) to obtain intermediate 83, which is light yellow oil with yield of 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)。
synthesis method according to example 24The title compound was obtained as a yellow oil from intermediate 83 and intermediate 76 in 19.7% yield,1H-NMR(400MHz,Acetone-d6)δ14.05(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]+。
example 766- (3-chloro-2, 4, 6-trihydroxy-5- (2-ethylbutanoyl) phenyl) -3-ethyl-5, 7-dihydroxy-8-methylchroman-4-one
Figure BDA0001845508230000442
1- (3-chloro-2, 4, 6-trihydroxyphenyl) -2-ethylbutane-1-one (84)
Reference to the synthesis of intermediate 83 gave intermediate 84 as a yellow oil in 73% yield,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 synthesis of example 24, the title compound was obtained from intermediate 84 and intermediate 76 as a yellow oil in 10.2% yield,1H-NMR(400MHz,Acetone-d6)δ14.06(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]+。
example 776, 6' -methylenebis (3-ethyl-5, 7-dihydroxy-8-methylchroman-4-one)
Figure BDA0001845508230000443
Referring to the synthesis of example 24, the title compound was obtained as intermediate 75 in 21.5% yield as a light yellow solid, mp: 208-;1H-NMR(400MHz,Acetone-d6)δ13.96(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]+。
example 788- (3-chloro-2, 4, 6-trihydroxy-5- (2-methylbutyryl) phenyl) -3-ethyl-7-hydroxy-5-methoxy-6-methylchroman-4-one
Figure BDA0001845508230000444
Referring to the synthesis of example 24, the title compound was obtained from intermediate 80 and intermediate 83 as a yellow oil in 29.6% yield,1H-NMR(400MHz,Acetone-d6)δ10.38(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]+。
example 791- (3-chloro-2, 4, 6-trihydroxy-5- (7- (6-hydroxy-4-methoxy-5-methyl-3-propylbenzo [ d ] isoxazole) methylphenyl) -2-methylbutyl-1-one
Figure BDA0001845508230000451
Referring to the synthesis of example 24, the title compound was obtained from intermediate 82 and intermediate 83 as a yellow solid in 10.7% yield, mp:157-,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]+。
example 801- (2,4, 6-Trihydroxyl-3- (7- (6-hydroxy-4-methoxy-5-methyl-3-propylbenzo [ d ] isoxazole) methyl) -5-methylphenyl) ethanone
Figure BDA0001845508230000452
Referring to the synthesis of example 24, the title compound was obtained from intermediate 82 and intermediate 9 as a yellow solid in 12.0% yield, mp: 193-;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]+。
example 816- (3-acetyl-2, 4, 6-trihydroxy-5-methylphenyl) -3-ethyl-5, 7-dihydroxy-8-methylchroman-4-one
Figure BDA0001845508230000453
Referring to the synthesis of example 24, the title compound was obtained as a yellow solid from intermediate 76 and intermediate 9 in 18.3% yield, mp: 207-;1H-NMR(400MHz,Acetone-d6)δ13.99(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]+。
example 826- (3-acetyl-5-chloro-2, 4, 6-trihydroxyphenyl) -3-ethyl-5, 7-dihydroxy-8-methylchroman-4-one
Figure BDA0001845508230000454
3-chloro-2, 4, 6-trihydroxyphenyl ethanone (85)
Reference to the synthesis of intermediate 83 gave intermediate 85,brown yellow 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 synthesis of example 24, the title compound was obtained from intermediate 76 and intermediate 85 as a yellow solid in 11.0% yield, mp: 190-;1H-NMR(400MHz,Acetone-d6)δ14.04(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]+。
example 836- (3-acetyl-5-bromo-2, 4, 6-trihydroxyphenyl) -3-ethyl-5, 7-dihydroxy-8-methylchroman-4-one
Figure BDA0001845508230000455
3-bromo-2, 4, 6-trihydroxyphenyl ethanone (86)
Reference to the synthesis of intermediate 83 gave intermediate 86 as a yellow solid in 29.7% yield,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 synthesis of example 24, the title compound was obtained from intermediate 76 and intermediate 86 as a yellow solid in 11.7% yield, mp: 210-;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]+。
example 846- (3-butyryl-5-chloro-2, 4, 6-trihydroxyphenyl) -3-ethyl-5, 7-dihydroxy-8-methylchroman-4-one
Figure BDA0001845508230000461
Referring to the synthesis of example 24, the title compound was obtained from intermediate 76 and intermediate 66 as a yellow solid in 11.0% yield, mp: 137-;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]+。
example 856- (3-propionyl-5-chloro-2, 4, 6-trihydroxyphenyl) -3-ethyl-5, 7-dihydroxy-8-methylchroman-4-one
Figure BDA0001845508230000462
3-chloro-2, 4, 6-trihydroxyphenyl acetone (87)
Reference to the synthesis of intermediate 83 gave intermediate 87 as a grey solid in 73% yield,1H-NMR(400MHz,DMSO-d6)δ14.31(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 synthesis of example 24, the title compound was obtained from intermediate 76 and intermediate 87 as a yellow solid in 13.3% yield, mp:145-,147 ℃,1H-NMR(400MHz,Acetone-d6)δ14.04(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]+。
example 861- (3-butanoyl-2, 6-dihydroxy-4-methoxy-5-methylphenyl) -5-chloro-2, 4, 6-trihydroxyphenyl) -2-methylbutyl-1-one
Figure BDA0001845508230000463
Referring to the synthesis of example 24, the title compound was obtained from intermediate 34 and intermediate 83 as a yellow oil in 47% yield,1H-NMR(300MHz,Acetone-d6)δ3.92(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]+。
example 871- (3-butyryl-2, 6-dihydroxy-4-methoxy-5-methylphenyl) -5-bromo-2, 4, 6-trihydroxyphenyl) -2-methylbutyl-1-one
Figure BDA0001845508230000464
1- (3-bromo-2, 4, 6-trihydroxyphenyl) -2-methylbutane-1-one (88)
Reference to the synthesis of intermediate 83 gave intermediate 88 as a yellow oil in 46% yield,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 synthesis of example 24, the title compound was obtained from intermediate 34 and intermediate 88 as a yellow oil in 43% yield,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]+。
example 883- (3-butanoyl-2, 6-dihydroxy-4-methoxy-5-methylphenyl) -2,4, 6-trihydroxy-5- (2-methylbutyryl) benzoic acid methyl ester
Figure BDA0001845508230000471
2,4, 6-Trihydroxyl-3- (2-methylbutyryl) benzoic acid methyl ester (89)
Reference to the synthesis of intermediate 83 gave intermediate 89 as a yellow oil in 61.1% yield,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)。
reference to realThe synthesis of example 24 was performed the title compound was obtained from intermediate 24 and intermediate 89 as a yellow solid in 50.0% yield, mp: 137-;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]+。
example 895, 5' -Methylenebis (2,4, 6-trihydroxy-3- (2-methylbutyryl) benzoic acid methyl ester)
Figure BDA0001845508230000472
Referring to the synthesis of example 24, the title compound was obtained from intermediate 89 as a yellow oil in 27.3% yield,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]+。
example 901- (3- (3, 5-dibromo-2, 4, 6-trihydroxyphenyl) -2, 4-dihydroxy-6-methoxy-5-methylphenyl) butyl-1-one
Figure BDA0001845508230000473
Referring to the synthesis of example 24, the title compound was obtained from intermediate 34 and intermediate 53 as a yellow solid in 12.0% yield, mp:178-,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]+。
example 911- (3- (3, 5-dichloro-2, 4, 6-trihydroxyphenyl) -2, 4-dihydroxy-6-methoxy-5-methylphenyl) butyl-1-one
Figure BDA0001845508230000474
Referring to the synthesis of example 24, the title compound was obtained from intermediate 34 and intermediate 50' as a yellow solid in 25.0% yield, mp:209-211 ℃;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]+。
example 923 methyl (3-butyryl-2, 6-dihydroxy-4-methoxy-5-methylphenyl) -5-chloro-2, 4, 6-trihydroxybenzoate
Figure BDA0001845508230000475
3-chloro-2, 4, 6-trihydroxybenzoic acid methyl ester (90)
Adding raw material (5mmol) into 50mL round-bottom flask, dissolving in 50mL chloroform, cooling to 0 deg.C, sequentially adding dropwise 500 μ L ethanol and sulfonyl chloride (5.125mmol), stirring at 0 deg.C for 3 hr, concentrating under reduced pressure, and adding siliconPurifying by gel column chromatography to obtain 90% white solid with yield of 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 synthesis of example 24, the title compound was obtained from intermediate 34 and intermediate 90 as a yellow solid in 28.8% yield, mp: 201-;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]+。
example 931- (3- (3-chloro-2, 4, 6-trihydroxy-5- (2-methylbutyryl) phenyl) -2, 4-dihydroxy-6-methoxy-5-methylphenyl) -2-methylbutyl-1-one
Figure BDA0001845508230000481
Referring to the synthesis of example 24, the title compound was obtained from intermediate 18 and intermediate 83 as a yellow oil in 13.2% yield,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]+。
example 941- (3-butanoyl-2, 6-dihydroxy-4-methoxy-5-methylphenyl) -5-chloro-2, 4, 6-trihydroxybenzaldehyde
Figure BDA0001845508230000482
3-chloro-2, 4, 6-trihydroxybenzaldehyde (91)
The intermediate 91 was obtained as a reddish brown solid in 82% yield according to the synthesis method of intermediate 1,1H-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 synthesis of example 24, the title compound was obtained from intermediate 34 and intermediate 91 in 9.4% yield as a yellow solid, mp:194-196 ℃;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]+。
example 951- (3-butyryl-2, 6-dihydroxy-4-methoxy-5-methylphenyl) -5-chloro-2, 4, 6-trihydroxypropiophenone
Figure BDA0001845508230000483
Referring to the synthesis of example 24, the title compound was obtained from intermediate 34 and intermediate 87 as a yellow solid in 14.4% yield, mp: 160-;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]+。
example 961- (3-butanoyl-2, 6-dihydroxy-4-methoxy-5-methylphenyl) -5-chloro-2, 4, 6-trihydroxyacetophenone
Figure BDA0001845508230000484
Referring to the synthesis of example 24, the title compound was obtained from intermediate 34 and intermediate 86 as a yellow solid in 7.9% yield, mp:187-189 ℃;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]+。
example 973- (3-butanoyl-2, 6-dihydroxy-4-methoxy-5-methylphenyl) -5-chloro-2, 4, 6-trihydroxybenzaldehyde oxime
Figure BDA0001845508230000485
3-chloro-2, 4, 6-trihydroxybenzaldehyde oxime (92)
In a 25mL round-bottom flask, hydroxylamine hydrochloride (8mmol) was added to Na2CO3To the aqueous solution of (4mmol), when the solid dissolved and no gas evolved, this aqueous solution was added to the starting material 91(2mmol) dissolved in 1mL of ethanol, heated to 75 ℃ for 3h, cooled, extracted, dried over anhydrous sodium sulfate, concentrated, purified by column chromatography (DCM/methanol ═ 100:1), and finally purified by column chromatography (DCM/methanol ═ 100:1)92 is obtained, light yellow solid is obtained, the yield is 37.1 percent,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 synthesis of example 24, the title compound was obtained as a yellow solid in 15.9% yield from intermediate 34 and intermediate 92, mp: 173-;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]+。
example 983- (3-butanoyl-2, 6-dihydroxy-4-methoxy-5-methylphenyl) -5-chloro-2, 4, 6-trihydroxybenzaldehyde methoxy oxime
Figure BDA0001845508230000491
3-chloro-2, 4, 6-trihydroxybenzaldehyde methoxyxime (93)
Reference to the synthesis of intermediate 92 gave intermediate 93 as a yellow solid in 73.3% yield,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 synthesis of example 24, the title compound was obtained from intermediate 34 and intermediate 93 as a yellow solid in 13.2% yield, mp:192-194 ℃;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]+。
example 996-fluoro-2-ethyl-8- ((3-ethyl-5, 7-dihydroxy-8-methyl-4-chroman-6-yl) methyl) 5, 7-dihydroxy-2-methyl chroman-4-one
Figure BDA0001845508230000492
1-fluoro-2, 4, 6-trihydroxybenzene (94)
To phloroglucinol (7.94mmol) CH at-45 deg.C3CN (100ml) solution was added portionwise to F-TEDA-BF4(9.52mmol), stirred for 0.5h, then stirred at room temperature overnight, concentrated under reduced pressure, and subjected to silica gel column chromatography (PE/EA ═ 2:1) to give intermediate 94 as a yellow solid in 82.1% yield,1H-NMR(400MHz,DMSO-d6)δ9.36(s,2H),8.87(s,1H),5.81(d,J＝6.5Hz,2H)。
6-fluoro-2-ethyl-5, 7-dihydroxy-2-methyl chroman-4-one (95) and 8-fluoro-2-ethyl-5, 7-dihydroxy-2-methyl chroman-4-one (96)
Reference to the synthesis of intermediate 48 gave intermediate 95 as a yellow solid in 45.1% yield,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)δ11.99(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 synthesis of example 24, the title compound was obtained from intermediate 76 and intermediate 95 as a yellow solid in 15.2% yield, mp:201-,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。
example 1002-Ethyl-6- ((3-ethyl-5, 7-dihydroxy-8-methyl-4-chroman-6-yl) methyl) -8-fluoro-5, 7-dihydroxy-2-methylchroman-4-one
Figure BDA0001845508230000493
Referring to the synthesis of example 24, the title compound was obtained from intermediate 76 and intermediate 96 as a yellow solid in 17.3% yield, mp:139-141 ℃;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。
example 1016-cyano-2-ethyl-8- ((3-ethyl-5, 7-dihydroxy-8-methyl-4-chroman-6-yl) methyl) -5, 7-dihydroxy-2-methylchroman-4-one
Figure BDA0001845508230000494
1-cyano-2, 4, 6-trihydroxybenzene (97)
Intermediate 52(0.9804mmol) and CuCN were dissolved in DMF (3ml) and reacted with microwave at 135 ℃ for 0.5h, concentrated under reduced pressure and chromatographed on silica gel (PE/EA ═ 1:1) to give intermediate 97 as yellow intermediate 97The yield of the solid is 51 percent,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-methylchroman-4-one (98) and 8-cyano-2-ethyl-5, 7-dihydroxy-2-methylchroman-4-one (99)
Reference to the synthesis of intermediate 48 gave intermediate 98 as a yellow solid in 30% yield,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 synthesis of example 24, the title compound was obtained from intermediate 76 and intermediate 98 as a yellow solid in 11.3% yield, mp:211-213 ℃;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。
example 1022-Ethyl-6- ((3-ethyl-5, 7-dihydroxy-8-methyl-4-chroman-6-yl) methyl) -8-cyano-5, 7-dihydroxy-2-methylchroman-4-one
Figure BDA0001845508230000501
Referring to the synthesis of example 24, the title compound was obtained from intermediate 76 and intermediate 99 as a yellow solid in 25.0% yield, mp: 206-;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。
example 1036- (4- (6-bromo-5, 7-dihydroxy-3-carbonyl-1-propylidene-1, 3-dihydroisobenzofuran) methyl) -3-ethyl-5, 7-dihydroxy-8-methylchroman-4-one
Figure BDA0001845508230000502
2-butyryl-3, 5-dihydroxybenzoic acid methyl ester (100)
Reference to the synthesis of intermediate 83 gave intermediate 100 as a yellow solid in 88.3% yield,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)。
2-butyryl-6-bromo-3, 5-dihydroxybenzoic acid methyl ester (101)
Reference to the synthesis of intermediate 52 gave intermediate 101 as a yellow solid in 42% yield,1H-NMR(400MHz,DMSO-d6)δ10.52(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 synthesis of example 24, the title compound was obtained from intermediate 76 and intermediate 101 as a yellow solid in 35.2% yield mp:207-,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。
example 1046-bromo-8- (6- (3-ethyl-5, 7-dihydroxy-8-methyl-4-chromanone) methyl) -5, 7-dihydroxy-2-methyl-2, 3-dihydroquinolin-4 (1H) -one
Figure BDA0001845508230000503
3- ((3, 5-Dimethoxyphenyl) aminobutanoic acid ethyl ester (102)
Stirring a solution of 3, 5-dimethoxyaniline (10mmol), ethyl acetoacetate (60mmol) and acetic acid (30 μ L) in dichloroethane (30mL) at room temperature for 20hs, adding sodium cyanoborohydride (40mmol), stirring for 20hs, stopping the reaction, adding a saturated sodium carbonate solution to a PH of 7, extracting, drying over anhydrous sodium sulfate, concentrating under reduced pressure, performing silica gel column chromatography (PE/EA ═ 10:1) to obtain intermediate 102 as a yellow solid in 85.2% yield,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) aminobutyric acid (103)
Intermediate 102(12mmol) in THF/H at room temperature2O (20 mL/20mL) was added lithium hydroxide (96mmol), stirred for 20hs, the reaction was stopped, 2N HCl solution was added to PH 7, extracted, dried over anhydrous sodium sulfate, concentrated under reduced pressure to give intermediate 103 as a 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)。
5, 7-dihydroxy-2-methyl-2, 3-dihydroquinolin-4 (1H) -one (104)
Hydrobromic acid acetic acid solution (8ml) was added to intermediate 103(12mmol) at room temperature, heated under reflux for 2hs, cooled, concentrated under reduced pressure, subjected to silica gel column chromatography (PE/EA ═ 2:1) to give 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)。
6-bromo-5, 7-dihydroxy-2-methyl-2, 3-dihydroquinolin-4 (1H) -one (105) and 8-bromo-5, 7-dihydroxy-2-methyl-2, 3-dihydroquinolin-4 (1H) -one (106)
Reference to the synthesis of intermediate 52 gave intermediate 105 as a yellow solid in 31% yield,1H-NMR(400MHz,DMSO-d6) δ 13.45(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, a yellow solid, in a yield of 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 synthesis of example 24, the title compound was obtained from intermediate 76 and intermediate 105 as a yellow solid in 27.8% yield, 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。
example 1058-bromo-6- (6- (3-ethyl-5, 7-dihydroxy-8-methyl-4-chromanone) methyl) -5, 7-dihydroxy-2-methyl-2, 3-dihydroquinolin-4 (1H) -one
Figure BDA0001845508230000511
Referring to the synthesis of example 24, the title compound was obtained from intermediate 76 and intermediate 106 as a yellow solid in 35.7% yield mp:210 and 212 ℃,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。
example 1066, 6' -methylenebis (8-bromo-5, 7-dihydroxy-2-methyl-2, 3-dihydroquinolin-4 (1H) -one)
Figure BDA0001845508230000512
Referring to the synthesis of example 1, the title compound was obtained from intermediate 106 as a yellow solid in 34.9% yield mp:202-,204 ℃,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。
example 1078-acetyl-10-bromo-3-ethyl-5, 7, 9-trihydroxy-13-methyl-6, 11-dihydro-2H-benzo [5,6] oxazepin [3,2] chroman-4 (3H) -one
Figure BDA0001845508230000513
4-methyl-2, 6-dihydroxy acetophenone (107)
The synthesis of intermediate 3 was referred to as intermediate 107, a 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-diacetoxyacetophenone (108)
Synthesis method according to reference example 22The intermediate 108 is obtained by the method, white solid is obtained, the yield is 96.0 percent,1H-NMR(400MHz,CDCl3)δ6.85(s,2H),2.44(s,3H),2.37(s,3H),2.27(s,6H)。
4-bromomethyl-2, 6-diacetoxyacetophenone (109)
NBS (11.76mmol) and AIBN (25mg) were added to a solution of intermediate 108(11.2mmol) in carbon tetrachloride (30ml) at room temperature under nitrogen, heated at reflux for 3hs, concentrated under reduced pressure, chromatographed on silica gel (PE/EA ═ 5:1) to give intermediate 109 as a yellow solid in 51.0% yield,1H-NMR(400MHz,CDCl3)δ7.12(s,2H),4.44(s,2H),2.48(s,3H),2.30(s,6H)。
4-bromomethyl-2, 6-dihydroxy acetophenone (110)
Concentrated sulfuric acid (2 drops) was added to a solution of intermediate 109(20mg) in methanol (1ml) at room temperature, heated at 50 ℃ for 1h, concentrated under reduced pressure, and subjected to silica gel column chromatography (PE/EA ═ 2:1) to give intermediate 110 as a yellow solid in 88.1% yield,1H-NMR(400MHz,DMSO-d6)δ11.87(s,2H),6.45(s,2H),4.53(s,2H),2.63(s,3H)。
4-bromomethyl-3-bromo-2, 6-dihydroxy acetophenone (111)
NBS (2.15mmol) was added to a solution of intermediate 110(2.1mmol) in dichloromethane (25ml) at room temperature, stirred for 1h, concentrated under reduced pressure, and subjected to silica gel column chromatography (PE/EA ═ 5:1) to give intermediate 111 as a yellow solid in 80.0% yield,1H-NMR(400MHz,Acetone-d6)δ6.77(s,1H),4.62(s,2H),2.75(s,3H)。
6- (3-acetyl-5-bromo-6- (bromomethyl) -2, 4-dihydroxyphenyl) -3-ethyl-5, 7-dihydroxy-8-methylchroman-4-one (112)
Referring to the synthesis of example 1, the title compound was obtained from intermediate 75 and intermediate 111 as a yellow solid in 89.1% yield,1H-NMR(400MHz,Acetone-d6)δ13.28(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)。
cesium carbonate (0.45mmol) was added to a solution of intermediate 112(0.036mmol) in acetone (20ml) at room temperature, stirred for 5hs, and filteredFiltration, concentration under reduced pressure, TLC plate chromatography (PE/EA. RTM. 5:1) gave the title compound as a yellow solid in 26.8% yield, mp:207-,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)δ205.6,200.3,163.1,158.8,157.9,156.9,155.0,142.0,121.3,114.2,106.2,105.3,103.2,102.6,70.4,69.8,45.8,33.5,19.9,18.2,11.67,8.2。ESI-MS:calcd for C22H21BrO7[M+H]+:477.05；found,477.26。
example 1088-acetyl-10-chloro-3-ethyl-5, 7, 9-trihydroxy-13-methyl-6, 11-dihydro-2H-benzo [5,6] oxazepin [3,2] chroman-4 (3H) -one
Figure BDA0001845508230000521
3-chloro-2, 6-dihydroxy-4-methylacetophenone (113)
To a solution of intermediate 107(0.03mmol) in acetonitrile (100ml) at room temperature were added NCS (0.03mmol) and aluminum chloride (200mg), stirred for 2hs, filtered, concentrated under reduced pressure, C18Silica gel column chromatography (PE/EA ═ 2:1) afforded intermediate 113 as a yellow solid in 87% yield,1H-NMR(400MHz,DMSO-d6)δ6.31(s,1H),2.62(s,3H),2.26(s,3H)。
3-chloro-4-methyl-2, 6-diacetoxyacetophenone (114)
Reference to the synthesis of intermediate 108 gave intermediate 114 as a yellow solid in 96.1% yield,1H-NMR(400MHz,DMSO-d6)δ7.28(s,1H),2.40(s,6H),2.33(s,3H),2.27(s,3H)。
3-chloro-4-bromomethyl-2, 6-diacetoxyacetophenone (115)
Reference to the synthesis of intermediate 109 gave intermediate 115 as a yellow solid in 93.1% yield,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)。
3-chloro-4-bromomethyl-2, 6-dihydroxy acetophenone (116)
Reference to the synthesis of intermediate 110 gave intermediate 116 as a yellow solid in 92.1% yield,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)。
reference to the synthesis of intermediate 112 gave intermediate 117 as a yellow solid in 67.1% yield, which was directly charged to the next step.
The title compound was obtained in 39.1% yield as a yellow solid according to the synthesis method of example 107 mp:221-,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。
example 1091- (9-acetyl-7-bromo-1, 8, 10-trihydroxy-3-methoxy-4-methyl-6, 11-dihydrodibenzo [ b, e ] oxepin-2-yl) chroman-1-one
Figure BDA0001845508230000522
Referring to the synthesis of example 107, the title compound was obtained from intermediate 6 and intermediate 111 as a yellow solid in 38.3% yield, mp:202 and 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。
example 11011-acetyl-9-bromo-5, 10, 12-trihydroxy-2, 2, 6-trimethyl-8, 13-dihydroxy-2H-benzo [5,6] oxazepin [2,3] chroman-4 (3H) -one
Figure BDA0001845508230000531
Referring to the synthesis of example 107, the title compound was obtained from intermediate 48a and intermediate 111 as a yellow solid in a yield of 36.1%, mp:196-,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。
example 11111-acetyl-9-chloro-5, 10, 12-trihydroxy-2, 2, 6-trimethyl-8, 13-dihydroxy-2H-benzo [5,6] oxazepin [2,3] chroman-4 (3H) -one
Figure BDA0001845508230000532
Referring to the synthesis of example 107, the title compound was obtained from intermediate 48a and intermediate 116 as a yellow solid in a yield of 32.8%, mp: 211-),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。
example 1128-acetyl-10-bromo-5, 7, 9-trihydroxy-2, 2, 13-trimethyl-6, 11-dihydroxy-2H-benzo [5,6] oxazepin [2,3] chroman-4 (3H) -one
Figure BDA0001845508230000533
Referring to the synthesis of example 107, the title compound was obtained from intermediate 48 a' and intermediate 111 as a yellow solid in a yield of 32.8%, mp:211-,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。
example 113N- (2- (4- ((3-butyryl-3, 5-dihydroxy-6-methyl-4- (2,4, 6-trihydroxy-3-methyl-5- (2-methylbutyryl) phenyl) phenoxy) methyl) -1H-1,2, 3-triazol-1-yl) ethyl) -5- ((3S,4S,6R) -2-hexahydro-1H- [3,4-d ] imidazol-4-yl) pentanamide
Figure BDA0001845508230000534
Dissolving 2-bromoethylamine (1mmol) in 2mL of water at normal temperature, adding sodium azide (3mmol), reacting at 80 ℃, stopping heating after 18h, cooling the reaction solution to room temperature, adding 10mg of potassium hydroxide at 0 ℃ under stirring, extracting with diethyl ether for three times after 5min, combining diethyl ether layers, and concentrating under reduced pressure to obtain colorless oily matter with yield: 60-80%.
Dissolving biotin (1mmol) and HOSu (1.07mmol) in 12mL of DMF, adding EDC.HCl (1.17mmol) while stirring at room temperature, continuing to stir at room temperature, after 24h, distilling off DMF under reduced pressure, washing the obtained residue with MeOH for 3 times to obtain biotin activated ester, yield: 89 percent.
Biotin activated ester (1mmol) and 2-azidoethylamine (1.5mmol) were dissolved in 3ml DMF, TEA (6mmol) was added and the reaction stirred at rt for 16h, DMF was evaporated under reduced pressure and purified by column chromatography (DCM/MeOH ═ 20:1) as a white solid 118 in yield: 84 percent，1H-NMR(300MHz,DMSO-d6)δ8.02(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 example 15(0.1mmol) were dissolved in 1mL of tert-butanol/water (v/v ═ 1:1), followed by the addition of aqueous sodium ascorbate (6mg/600 μ L), followed by a solution of copper sulfate pentahydrate (10mg/800 μ L), followed by reaction at 45 ℃ and detection by LC-MS after 8h indicated that the starting material was substantially reacted, heating was stopped, 4mL of water was added, extraction was performed 3 times with ethyl acetate, the combined ethyl acetate layers were concentrated under reduced pressure and purified by silica gel column chromatography (DCM/MeOH ═ 10:1) to afford the title compound as a yellow solid in yield: 30%, mp 148-,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。
example 114N- (2- (4- ((3- (2-methylbutyryl) -3, 5-dihydroxy-6-methyl-4- (2,4, 6-trihydroxy-3-methyl-5- (2-methylbutyryl) phenyl) phenoxy) methyl) -1H-1,2, 3-triazol-1-yl) ethyl) -5- ((3S,4S,6R) -2-hexahydro-1H- [3,4-d ] imidazol-4-yl) pentanamide
Figure BDA0001845508230000541
The title compound was obtained in 40% yield from example 113 as a white solid, mp 148-,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。
example 1157-chloro-5- ((3-ethyl-5, 7-dihydroxy-8-methyl-4-chroman-6-yl) methyl) -6, 8-dihydroxy-1, 3,3a,9 a-tetrahydrocyclopenta [ b ] chroman-9 (2H) -ene
Figure BDA0001845508230000542
7-chloro-6, 8-dihydroxy-1, 3,3a,9 a-tetrahydrocyclopenta [ b ] chroman-9 (2H) -ene (119) and 5-chloro-6, 8-dihydroxy-1, 3,3a,9 a-tetrahydrocyclopenta [ b ] chroman-9 (2H) -ene (120)
Reference to the synthesis of intermediate 48 gave intermediate 119 as a yellow solid in 42.9% yield,1H-NMR (400MHz, Acetone) delta 12.93(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 intermediate 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)。
the title compound was synthesized from intermediate 76 and the title compound by the method of example 24Intermediate 119 was obtained as a yellow solid in 25.4% yield, mp: 187-.1H-NMR(400MHz,DMSO-d6)δ12.89(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。
Example 1165-chloro-7- ((3-ethyl-5, 7-dihydroxy-8-methyl-4-chroman-6-yl) methyl) -6, 8-dihydroxy-1, 3,3a,9 a-tetrahydrocyclopenta [ b ] chroman-9 (2H) -ene
Figure BDA0001845508230000543
Referring to the synthesis of example 24, the title compound was obtained from intermediate 76 and intermediate 120 as a yellow solid in 22.7% yield, mp198 ℃.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。
Example 1176-chloro-8- ((3-ethyl-5, 7-dihydroxy-8-methyl-4-chroman-6-yl) methyl-5, 7-dihydroxy-2-methyl-4H-chroman-4-one
Figure BDA0001845508230000551
2,4, 6-trihydroxyacetophenone (121)
The intermediate 121 was obtained as a yellow solid in 85% yield according to the synthesis method of intermediate 3,1H-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-one (122)
Intermediate 121(12.5mmol) was dissolved in 10mL of acetic anhydride, followed by addition of sodium acetate (37.5mmol), reflux reaction for 2h, cooling, addition of 30mL of water, extraction with ethyl acetate, and concentration under reduced pressure. The concentrated solid was dissolved in an aqueous solution (30mL) of sodium carbonate (62.5mmol), refluxed for 3 hours, concentrated under reduced pressure, and subjected to silica gel column chromatography (ethyl acetate/petroleum ether ═ 1: 4) to obtain a pale yellow solid 122, yield: the mass ratio of the mixture is 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)。
6-bromo-5, 7-dihydroxy-2-methyl-4H-chroman-4-one (123)
Intermediate 122(1.6mmol) was dissolved in 15mL tetrahydrofuran, NBS (1.7mmol) was added portionwise at room temperature, reaction was continued for 1h, concentration under reduced pressure, C18 silica gel column chromatography (water/methanol 95: 5-0: 100) gave 123 as a pale yellow solid in yield: the content of the active carbon is 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 synthesis of example 24, the title compound was obtained as a yellow solid from intermediate 76 and intermediate 123 in 30.8% yield, mp197-200 ℃.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。
Example 1186-bromo-2-ethyl-8- ((3-ethyl-5, 7-dihydroxy-8-methyl-4-chroman-6-phenyl) methyl) -5, 7-dihydroxy-2-methylchroman-4-one
Figure BDA0001845508230000552
Referring to the synthesis of example 1, benzaldehyde was added and the title compound was obtained from intermediate 75 and intermediate 54a as a yellow solid in 22.8% yield mp 195-.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。
Example 119 bis (3-ethyl-5, 7-dihydroxy-8-methylchroman-4-one) -6, 6' -methylbenzene
Figure BDA0001845508230000553
Referring to the synthesis of example 118, the title compound was obtained from intermediate 75 as a yellow solid in 39.8% yield mp 167-.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。
Example 1206-bromo-2-ethyl-8- ((3-ethyl-5, 7-dihydroxy-8-methyl-4-chroman-6- (4-fluorophenyl)) methyl) -5, 7-dihydroxy-2-methylchroman-4-one
Figure BDA0001845508230000554
Referring to the synthesis of example 1, 4-fluorobenzaldehyde was added and the title compound was obtained as a yellow solid from intermediate 75 and intermediate 54a in 21.6% yield mp 201-.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。
Example 121 bis (3-ethyl-5, 7-dihydroxy-8-methylchroman-4-one) -6, 6' -methyl (4-fluorobenzene)
Figure BDA0001845508230000561
Referring to the synthesis of example 120, the title compound was obtained as intermediate 75 in 18.6% yield as a yellow solid, mp 198-.1H-NMR(400MHz,DMSO-d6)δ7.22(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。
Example 1228-acetyl-6- (3-butanoyl-2, 6-dihydroxy-4-methoxy-5-methylphenyl) -3-fluoro-5, 7-dihydroxy-4-methyl-2H-chroman-2-one
Figure BDA0001845508230000562
3-fluoro-5, 7-dihydroxy-4-methyl-2H-chroman-2-one (124)
Phloroglucinol (0.1mol) and ethyl 2-fluoroacetoacetate (0.1mol) were dissolved in 150ml of anhydrous ethanol, boron trifluoride ether solution (0.3mol) was added, reflux reaction was carried out, LC-MS tracking detection was carried out, concentration under reduced pressure and filtration were carried out, and the obtained solid was washed with saturated aqueous sodium bicarbonate solution and water in this order to obtain a final yellow solid 124 with a yield of 84.0%.1H-NMR(400MHz,DMSO-d6)δ10.59(s,1H),10.23(s,1H),6.32(d,J＝2.4Hz,1H),6.21(d,J＝2.4Hz,1H),2.45(s,3H)。
8-acetyl-3-fluoro-5, 7-dihydroxy-4-methyl-2H-chroman-2-one (125)
Intermediate 124(14mmol) was mixed in 5mL nitromethane, aluminum trichloride (68mmol) was added carefully with stirring at room temperature, stirring was continued until the reaction mixture was in solution, acetic anhydride (15mmol) was slowly added dropwise, reaction was carried out at 100 ℃ for 1h, cooling was carried out, 4M HCl (30mL) and ethyl acetate (100mL) were added thereto, vigorous stirring, extraction, drying, concentration, and the residual solid was washed with ethyl acetate to give 125 as a white solid in 56.3% yield.1H-NMR(400MHz,DMSO-d6)δ12.97(s,1H),11.75(s,1H),6.37(s,1H),2.66(s,3H)。
Referring to the synthesis of example 24, the title compound was obtained from intermediate 34 and intermediate 125 as a yellow solid in 21.6% yield, mp202-204 ℃.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。
Example 1238-bromo-6- (3-butanoyl-2, 6-dihydroxy-4-methoxy-5-methylphenyl) -5, 7-dihydroxy-4-methyl-2H-chroman-2-one
Figure BDA0001845508230000563
5, 7-dihydroxy-4-methyl-2H-chroman-2-one (126)
The synthesis of reference intermediate 124 gave intermediate 126 as a yellow solid in 75.0% yield.1H-NMR(400MHz,DMSO-d6)δ10.50(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)。
8-bromo-5, 7-dihydroxy-4-methyl-2H-chroman-2-one (127)
Reference to the synthesis of intermediate 123 gave intermediate 127 as a yellow solid in 69.2% yield.1H-NMR(400MHz,Acetone-d6)δ9.20(s,2H),6.54(s,1H),5.97(s,1H),2.61(s,3H)。
Referring to the synthesis of example 24, the title compound was obtained as a yellow solid in 15.3% yield from intermediate 76 and intermediate 127, mp 195-197 ℃.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。
Example 1248-acetyl-6- (3-butanoyl-2, 6-dihydroxy-4-methoxy-5-methylphenyl) -4-ethyl-3-fluoro-5, 7-dihydroxy-2H-chroman-2-one
Figure BDA0001845508230000571
3-fluoro-5, 7-dihydroxy-4-ethyl-2H-chroman-2-one (128)
The synthesis procedure referenced for intermediate 124 gave intermediate 128 as a yellow solid in 91.0% yield.1H-NMR(400MHz,DMSO-d6)δ10.64(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)。
8-acetyl-3-fluoro-5, 7-dihydroxy-4-ethyl-2H-chroman-2-one (129)
Reference to the synthesis of intermediate 125 gave intermediate 129 as a yellow solid in 67.1% yield.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 synthesis of example 24, the title compound was obtained from intermediate 34 and intermediate 129 as a yellow solid in 31.3% yield, mp204-206 ℃.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。
Example 1258-acetyl-6- (3-butanoyl-2, 6-dihydroxy-4-methoxy-5-methylphenyl) -3-fluoro-5, 7-dihydroxy-4-propyl-2H-chroman-2-one
Figure BDA0001845508230000572
3-fluoro-5, 7-dihydroxy-4-propyl-2H-chroman-2-one (130)
The synthesis procedure referenced for intermediate 124 gave intermediate 130 as a yellow solid in 88.0% yield.1H-NMR(400MHz,DMSO-d6)δ10.63(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)。
8-acetyl-3-fluoro-5, 7-dihydroxy-4-propyl-2H-chroman-2-one (131)
The synthesis of reference intermediate 125 gave intermediate 131 as a yellow solid in 62.1% yield.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 synthesis of example 24, the title compound was obtained from intermediate 34 and intermediate 131 as a yellow solid in 35.6% yield, mp207-209 ℃.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。
Example 1268-bromo-6- (3-butanoyl-2, 6-dihydroxy-4-methoxy-5-methylphenyl) -3-fluoro-5, 7-dihydroxy-4-methyl-2H-chroman-2-one
Figure BDA0001845508230000573
8-bromo-3-fluoro-5, 7-dihydroxy-4-methyl-2H-chroman-2-one (132)
The synthesis procedure referenced for intermediate 123 gave intermediate 132 as a yellow solid in 72.3% yield.1H-NMR(400MHz,Acetone-d6)δ11.22(s,1H),10.97(s,1H),6.72(s,1H),2.51(s,3H)。
Referring to the synthesis of example 24, the title compound was obtained from intermediate 34 and intermediate 132 as a yellow solid in 21.5% yield, mp183-186℃。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。
Example 1274-acetyl-2- (3-butyryl-2, 6-dihydroxy-4-methoxy-5-methylphenyl) -1, 3-dihydroxy-7, 8,9, 10-tetrahydro-6H-benzo [ c ] chroman-6-one
Figure BDA0001845508230000581
1, 3-dihydroxy-7, 8,9, 10-tetrahydro-6H-benzo [ c ] chroman-6-one (133)
The synthesis procedure referenced for intermediate 124 gave intermediate 133 as a yellow solid in 83.0% yield.1H-NMR(400MHz,DMSO-d6)δ10.34(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-1, 3-dihydroxy-7, 8,9, 10-tetrahydro-6H-benzo [ c ] chroman-6-one (134)
The synthesis of reference intermediate 125 gave intermediate 134 as a yellow solid in 72.6% yield.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 synthesis of example 24, the title compound was obtained from intermediate 34 and intermediate 134 as a yellow solid in 29.4% yield, mp210-212 ℃.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。
Example 1288-acetyl-6- ((3-ethyl-5, 7-dihydroxy-8-methyl-4-chroman-6-yl) methyl) -3-fluoro-5, 7-dihydroxy-4-methyl-2H-chroman-2-one
Figure BDA0001845508230000582
Referring to the synthesis of example 24, the title compound was obtained from intermediate 76 and intermediate 125 as a yellow solid in 21.6% yield, mp198-200 ℃.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。
Example 1298-bromo-6- ((3-ethyl-5, 7-dihydroxy-8-methyl-4-chroman-6-yl) methyl) -3-fluoro-5, 7-dihydroxy-4-methyl-2H-chroman-2-one
Figure BDA0001845508230000583
Referring to the synthesis of example 24, the title compound was obtained from intermediate 76 and intermediate 132 as a yellow solid in 19.8% yield, mp190-192 ℃.1H-NMR(400MHz,DMSO-d6)δ13.50(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。
Example 1308-acetyl-6- ((6-bromo-2-ethyl-5, 7-dihydroxy-2-methyl-4-chroman-8-yl) methyl) -3-fluoro-5, 7-dihydroxy-4-methyl-2H-chroman-2-one
Figure BDA0001845508230000584
Referring to the synthesis of example 24, the title compound was obtained from intermediate 54a and intermediate 125 as a yellow solid in 18.1% yield mp 209-.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。
Example 131 in vitro BCG and Mtb pHIBDetection of
1) Bacillus Calmette-Guerin (BCG) or Mycobacterium tuberculosis (Mtb) (BCG-pHGFP or H) transfected with green fluorescent protein (pHGFP) is used37Rv-pHGFP), adding a bacterial culture medium (OD) to a 96-well plate5800.2), phosphate-citrate-tyloxapol buffer and different concentrations of test compound. After a certain time, the fluorescence values at the excitation wavelengths of 395nm and 475nm and at the emission wavelengths of 510nm are respectively read, and the pH value is calculated by the ratio of the fluorescence values (395nm/475nm) according to the corresponding curvesIBThe value is obtained. If the pH is higherIBAnd (4) the peptide is identified as an active compound after being less than 6.0.
2) Using DMSO as a negative control and natural agrimophol as a positive control, compounds were first evaluated for p in a single high dose (12.5. mu.M) versus BCGHIBInhibiting the activity.
3) For active compounds, subsequent reduction of compound concentration for multiple dose screening, to find compounds capable of reducing the pH of BCG or MtbIBDown to a minimum concentration of 6.0.
As can be seen from the data in table 1, the example compounds exhibit better activity in lowering the pH in bacteria, in particular analogs of the coumarine ring.
Table 1: the compound reduces the pH in BCG or Mtb bacteria to a minimum concentration of less than 6.0
Figure BDA0001845508230000591
Figure BDA0001845508230000601
No detection of ND
Example 132 in vitro liver microsome stability assay
Equal amounts of 300 μ L plasma were transferred to 1.1mL tubes (n ═ 1); preincubation at 37 ℃ for 15 minutes followed by addition of 3.0 μ L of positive control tetracaine (100 μ M in DMSO) and test compound (1mM in acetonitrile); at time points of 0min,5min,15min,30min,1h and 2h, 200. mu.L of each sample was taken out of each tube, 200. mu.L of the quenching solution was added, and vigorous vortexing was performed for 1 min; then centrifuging the sample at 4 ℃ at 4000rpm for 15min, and transferring 100 supernatants into a 0.65mL tube; LCMS analysis.
The results in table 2 show that some of the compounds show better metabolic stability in human liver microsomes relative to murine liver microsomes results, due to differences between animal species. Metabolic stability is coumarin analogue (example compound 122) > linear structure compound (example compounds 3 and 5) > chromanone structure compound (example compound 69). Meanwhile, the analysis finds that the unsaturated ring and the chromanone of the agrimophol are main metabolic sites. Also, the results of table 3 show that the main metabolic enzyme of the example compound in human liver microsomes is cytochrome P450 subtype 3a 4.
Table 2: evaluation of the Metabolic stability of Compounds in human and murine liver microsomes
Figure BDA0001845508230000602
Figure BDA0001845508230000611
No detection of ND
Table 3: EXAMPLE Compound 122 cytochrome P450 subtype evaluation in human liver microsomes
Figure BDA0001845508230000612
Therefore, the compound has long half-life period in human liver microsomes and high metabolic stability.
Example 133 HepG2 evaluation of the cytotoxicity test
HepG2 cells were seeded into RPMI1640 medium (100. mu.L, 5% FBS and 2mM L-glutamine) in 96-well microtiter plates and incubated for 24 h. The compounds were added at different concentrations and incubated for 48h (37 ℃, 5% CO)295% air and 100% relative humidity), 50 μ L of cold TCA (10% TCA) was added, incubation was continued for 1h at 4 ℃, the supernatant was discarded, the plate was washed 5 times with water and air dried, Sulforhodamine B solution (100 μ L, 0.4% (v/v) in 1% acetic acid) was added, incubation was continued for 10min at room temperature, staining, washing 5 times with 1% acetic acid to remove unbound dye and air dried, followed by solubilization with 10mM trizma and reading of the absorbance at 515nm with Multiscan Spectrum. The percent inhibition of cell growth was calculated as follows: [ (C-T)/C]100, C is the growth number of the control group and T is the growth number of the test drug group. The results in fig. 1 show that compound 122, which is more active and metabolically stable, also has lower cytotoxicity and higher SI values. Table 4 shows the EC of agrimophol and the more active and metabolically stable example compounds 122 and 12850,LD50And the calculation result of the SI value, wherein SI is a selectivity index,the value was LD50/EC 50. The calculations show that the SI values of example compounds 122 and 128 are much greater than 10, indicating that the compounds of the examples of the invention have lower cytotoxicity.
Table 4: agrimophol and EC of example Compounds 122 and 12850,LD50And calculation of SI value
Example numbering 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
EXAMPLE 134 in vitro evaluation of Mtb and clinically isolated MDR-Mtb and XDR-Mtb survival
Wild-type Mtb: culture Medium for wild type Mtb with Pbit-Tyl-4.5 washes 2 times, centrifugation 10min (120g), followed by dilution of OD580The value was 0.1, 200. mu.L were pipetted into a 96-well plate, compounds at different concentrations were added, incubated for 6 days at 37 ℃, PBS washed 2 times, Mtb were collected, plated (7H11agar), incubated at 37 ℃ and counted. DMSO and natural agrimophol were used as negative and positive controls, respectively.
MDR-Mtb and XDR-Mtb: the strain obtained by clinical isolation was washed 2 times with Pmit-Tyl-4.5, centrifuged for 10 minutes (120g), and then the OD was diluted580The value was 0.2, 200. mu.L was pipetted into a 96-well plate, compounds of different concentrations were added, incubated at 37 ℃ for 6 days, PBS washed 2 times, the strains were collected, plated (7H11agar), incubated at 37 ℃ for 3 days, and the fluorescent indicator 9, 9-dimethyl-2-nitro-7-propyl-10, 11-dihydrofuran [2,3-f ] was added]Pyran [2,3-h ]]Chroman-5 (9H) -one, the fluorescence value was measured at wavelengths of 390nm for excitation and 470nm for emission, and the inhibition ratio was calculated.
The results in FIG. 2 show that example compound 122 was able to reduce Colony Forming Units (CFU) by 1.5 orders of magnitude at 0.78 μ M and 3.125 μ M by 3 orders of magnitude. While agrimophol and example compound 128 were able to reduce Colony Forming Units (CFU) by 1 order of magnitude at 3.125. mu.M. While example Compound 122 and Agrimophol inhibit the MIC for MDR-Mtb growth90Value 1.56. mu.M and MIC for inhibition of XDR-Mtb growth90The value was 6.25. mu.M.
Therefore, the compound has higher activity of inhibiting the growth of Mtb and activity of inhibiting the growth of MDR-Mtb and XDR-Mtb.
In the description herein, references to the description of the term "one embodiment," "some embodiments," "an example," "a specific example," or "some examples," etc., mean that a particular feature, structure, material, or characteristic described in connection with the embodiment or example is included in at least one embodiment or example of the invention. In this specification, the schematic representations of the terms used above do not necessarily refer to the same embodiment or example. Furthermore, the particular features, structures, materials, or characteristics described may be combined in any suitable manner in any one or more embodiments or examples.
While embodiments of the invention have been shown and described, it will be understood by those of ordinary skill in the art that: various changes, modifications, substitutions and alterations can be made to the embodiments without departing from the principles and spirit of the invention, the scope of which is defined by the claims and their equivalents.

Claims (7)

1. A compound having a structure represented by one of the following or a stereoisomer, tautomer, pharmaceutically acceptable salt thereof,
Figure FDA0003032828890000011
Figure FDA0003032828890000021
Figure FDA0003032828890000031
2. a pharmaceutical composition comprising a compound of claim 1.
3. The pharmaceutical composition of claim 2, further comprising a pharmaceutically acceptable adjuvant, excipient, carrier, vehicle, or combination thereof.
4. The pharmaceutical composition of claim 2, further comprising an additional therapeutic agent selected from the group consisting of an anti-tuberculosis agent, an anti-HIV agent, and an agent for treating diabetes.
5. The pharmaceutical composition of claim 4, wherein the anti-tuberculosis drug is isoniazid, rifampin, ethambutol, or pyrazinamide.
6. The pharmaceutical composition of claim 4, wherein the anti-HIV drug is efavirenz or nevirapine.
7. Use of a compound according to claim 1 or a pharmaceutical composition according to any one of claims 2-6 for the preparation of a medicament for the prevention and/or treatment of tuberculosis in children, pulmonary tuberculosis, intestinal tuberculosis, lymphoid tuberculosis, bone tuberculosis, renal tuberculosis, tuberculous peritonitis, tuberculous meningitis, drug-sensitive tuberculosis, multi-drug resistant tuberculosis, extensively drug resistant tuberculosis, latent tuberculosis, HIV co-infected tuberculosis or diseases associated with mycobacterium tuberculosis infection.
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