CN117396580A - Boron-containing cyclic light-emitting compound and color conversion film comprising the same - Google Patents

Boron-containing cyclic light-emitting compound and color conversion film comprising the same Download PDF

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CN117396580A
CN117396580A CN202280036055.0A CN202280036055A CN117396580A CN 117396580 A CN117396580 A CN 117396580A CN 202280036055 A CN202280036055 A CN 202280036055A CN 117396580 A CN117396580 A CN 117396580A
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郑世俊
杰弗瑞·R·汉默克
丁新亮
王鹏
蔡洁
刘协
姚汀莎
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Nitto Denko Corp
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Nitto Denko Corp
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Priority claimed from PCT/US2022/076912 external-priority patent/WO2023049828A1/en
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Abstract

The present invention relates to yeast cells that are genetically modified to reduce their propensity to degrade specific platform chemicals (e.g., acrylic acid), and to methods of making and using such yeast cells to produce acrylic acid and other compounds.

Description

Boron-containing cyclic light-emitting compound and color conversion film comprising the same
Cross Reference to Related Applications
The present application claims priority from U.S. provisional application No.63/248,863 filed on day 27 of 9 in 2021 and U.S. provisional application No.63/278,944 filed on day 11 in 2021, both of which are incorporated herein by reference in their entireties.
Background
Unless otherwise indicated herein, the details described herein are not prior art to the claims in this application and are not admitted to be prior art by inclusion in this section.
In color reproduction, a gamut or gamut (color gamut) is a specific complete subset of the colors available on a device such as a television or display. For example, adobe was developed in a wide-area (wide-gamut) color space realized by using pure spectral primaries TM Red Green Blue (RGB) to provide a wider color gamut and to provide a more realistic representation of visible colors viewed through the display. It is believed that devices that can provide a wider color gamut can enable the display to present brighter colors.
As high definition large screen displays become more popular, the demand for higher performance, thinner and powerful displays is also increasing. Current Light Emitting Diodes (LEDs) are obtained by exciting a green, red or yellow phosphor with a blue light source to obtain a white light source. However, the full width at half maximum (FWHM) of the emission peaks of the green and red phosphors is currently quite large, typically greater than 40nm, resulting in overlapping green and red spectra and presenting colors that cannot be fully distinguished from each other. This overlap results in poor color reproduction and degradation of the color gamut.
In order to correct the degradation of the color gamut, a method of using a film containing quantum dots in combination with an LED has been developed. However, quantum dots have various drawbacks including toxicity, inefficiency, expensive encapsulation processes, and dimensional uniformity.
Accordingly, there is a need for improving the performance of color conversion films, backlight units, and display devices.
Disclosure of Invention
The photoluminescent compounds described herein can be used to improve the contrast between distinguishable colors in televisions, computer displays, smart devices, and any other device that utilizes a color display. The photoluminescent composite of the present invention includes a color conversion dye composite having good blue absorbance and a narrow emission bandwidth, wherein the full width at half maximum [ FWHM ] of the emission band is less than 40nm. In some embodiments, the photoluminescent compound absorbs light at a first wavelength and emits light at a second wavelength that is longer than the first wavelength. The photoluminescent compounds disclosed herein can be used in light emitting devices with color conversion films. The color conversion film of the present invention reduces color degradation by reducing overlap within the color spectrum, resulting in high quality color reproduction.
Some embodiments include a photoluminescent compound, wherein the photoluminescent compound may comprise: a naphthalimide derivative that absorbs blue light; a linking complex comprising an unsubstituted ester, a substituted ester, an unsubstituted ether, or a substituted ether; and a ring-locked boron-dipyrromethene (BODIPY) moiety. In some embodiments, the linking complex can covalently link the naphthalimide derivative to the ring-locked BODIPY moiety. In many embodiments, the ring-locked BODIPY moiety absorbs energy from the naphthalimide derivative at a first excitation wavelength and emits light energy at a second, higher wavelength. In various embodiments, the photoluminescent compound has an emission quantum yield greater than 80%.
In some embodiments, the photoluminescent complex can have an emission band having a full width half maximum [ FWHM ] of at most 40 nm.
In many embodiments, the photoluminescent compound may have a Stokes shift (i.e., the difference between the excitation peak of the blue light absorbing moiety and the emission peak of the BODIPY moiety) equal to or greater than 45 nm.
Many embodiments include a color conversion film, wherein the color conversion film can include: a transparent substrate layer; a color conversion layer, wherein the color conversion layer comprises a resin matrix; and at least one photoluminescent composite as described herein dispersed in the resin matrix. In some embodiments, the thickness of the color conversion film may be between 1 μm and about 200 μm. In many embodiments, the color conversion films of the present invention can absorb blue light in the range of 400nm to about 480nm and emit light in the wavelength range of 510nm to about 560 nm. Another embodiment includes a color conversion film that can absorb blue light in the range of 400nm to about 480nm and emit light in the wavelength range of 580nm to about 670 nm. In various embodiments, the color conversion film may further include a transparent substrate layer. In some embodiments, the transparent substrate layer may include two opposing surfaces, wherein the color conversion layer is disposed on one of the opposing surfaces.
In some embodiments, the color conversion film may further include a singlet oxygen quencher. In some embodiments, the color conversion film may further include a radical scavenger.
Many embodiments include a method of preparing a color conversion film, the method comprising: dissolving the photoluminescent composite and the binder resin described herein in a solvent; and applying the mixture to one of the opposing surfaces of the transparent substrate.
Some embodiments include a backlight unit including a color conversion film as described herein.
Some embodiments include a display device including a backlight unit as described herein.
The present application provides a photoluminescent composite having excellent color gamut and luminescent properties; a method of manufacturing a color conversion film using a photoluminescent compound, and a backlight unit including the color conversion film. These and other embodiments are described in more detail below.
Drawings
FIG. 1 is a graph depicting the absorption spectrum and emission spectrum of one embodiment of a photoluminescent compound (PLC-1).
FIG. 2 is a graph depicting the absorption spectrum and emission spectrum of one embodiment of a photoluminescent compound (PLC-2).
FIG. 3 is a graph depicting the absorption spectrum and emission spectrum of one embodiment of a photoluminescent compound (PLC-3).
Detailed Description
The present invention relates to a photoluminescent composition for a color conversion film, a backlight unit, and a display device including the backlight unit. Photoluminescent complexes can be used to improve and enhance the transmittance of one or more desired emission bandwidths within the color conversion film. In some embodiments, the photoluminescent compound can simultaneously increase the transmittance of the desired first emission bandwidth and decrease the transmittance of the second emission bandwidth. In some embodiments, the present invention describes a photoluminescent complex that can improve the contrast or intensity between two colors, thereby increasing their differentiation from each other.
In some embodiments, boron-dipyrromethene (BODIPY) compounds are used as emissive materials in place of the use of quantum dots. BODIPY complexes can have narrow FWHM, high fluorescence efficiency, stability to both moisture and oxygen, and low production costs. The current BODPY strategy has some drawbacks, such as low absorption of blue LED light (e.g., 450 nm), resulting in inefficient conversion of blue LED light to green and red light, and a broad FWHM when used in color conversion films. In some embodiments, the BODIPY compounds disclosed herein overcome these limitations.
As used herein, a compound or chemical structure may include one or more substituents when the compound or structure is referred to as "substituted". The substituted groups are derived from an unsubstituted parent structure wherein one or more hydrogen atoms on the parent structure have been independently replaced by one or moreAnd (3) substituting the substituent. In some embodiments, the substituents may independently be F, cl, br, I, C 0-7 H 1-15 O 1-2 N 0-2 、C 0-7 H 1-15 O 0-2 N 1-2 Optionally substituted alkyl (including unsubstituted alkyl, e.g. methyl, ethyl, C 3 Alkyl, C 4 Alkyl groups or the like, fluoroalkyl groups such as CF 3 Etc.), alkenyl or C 3-7 A heteroalkyl group.
The term "alkyl" as used herein refers to a hydrocarbon group that does not contain a carbon-carbon double bond or a carbon-carbon triple bond, and includes straight, branched, or cyclic alkyl groups.
"olefinic" moiety refers to a group having at least one carbon-carbon double bond (-c=c-) and includes straight chain, branched or cyclic olefinic moieties.
"alkyne" moiety refers to a group having at least one carbon-carbon triple bond (-c≡c-) and includes straight, branched or cyclic alkyne moieties.
In some embodiments, the alkyl moiety may have from 1 to 6 carbon atoms (whether or not they are present herein), a numerical range such as "1 to 6" referring to each integer within the given range: for example, "1 to 6 carbon atoms" means that an alkyl group may have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 6 carbon atoms, but the present definition also covers the occurrence of the term "alkyl" in which no numerical range is specified. The alkyl groups of the compounds specified herein may be designated as "C 1-6 Alkyl "or similar designations. By way of example only, "C 1-6 Alkyl "means that 1 to 6 carbon atoms are present in the alkyl chain, i.e., the alkyl chain is methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, or the like. Thus C 1-6 Alkyl groups include, for example, C 1-2 Alkyl, C 3-4 Alkyl, C 4-5 Alkyl or C 5-6 An alkyl group. Alkyl groups may be substituted or unsubstituted. Typical alkyl groups include, but are in no way limited to: methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl, ethenyl, propenyl, butenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.
Typical alkenyl groups include, but are not limited to, ethenyl, propenyl, butenyl, and the like.
The term "heteroalkyl" as used herein refers to an alkyl group, as defined herein, in which one or more of the constituent carbon and/or hydrogen atoms have been replaced with nitrogen, oxygen or sulfur. Examples include, but are not limited to, -CH 2 -O-CH 3 、-CH 2 -CH 2 -O-CH 3 、-CH 2 -N(CH 3 )-CH 3 、-CH 2 -CH 2 -NH-CH 3 、-CH 2 -CH 2 -N(CH 3 )-CH 3 、-CH 2 -S-CH 2 -CH 3 、-CH 2 -NH-O-CH 3 Etc.
The term "aromatic" refers to a planar ring having a delocalized pi-electron system comprising 4n+2 pi electrons, wherein n is an integer. The aromatic ring may be formed from five, six, seven, eight, nine or more than nine atoms. The aromatic ring may be optionally substituted. The term "aromatic" includes both carbocyclic aryl (e.g., phenyl) and heterocyclic aryl (or "heteroaryl" or "heteroaromatic") groups (e.g., pyridine). The term includes monocyclic or fused ring polycyclic (i.e., rings sharing adjacent pairs of carbon atoms) groups.
The term "hydrocarbon ring" refers to a monocyclic or polycyclic ring system which contains only carbon and hydrogen and which may be saturated. Monocyclic carbocycles include groups having 3 to 12 carbon atoms. Illustrative examples of monocyclic groups include the following moieties:
etc.
Illustrative examples of polycyclic groups include the following moieties:
[ bicyclo octane]、/>[ dicyclopentane ]]、/>[ bicycloheptane]、[ bicycloheptane]、/>[ dicyclohexyldecane ]]、/>[ decalin ]]、/>[ octahydropentalene ]]、/>[ octahydroindene ]]、[ hexahydroindene ]]、/>[1,2,3, 4-tetrahydronaphthalene]、[2, 3-dihydro-1H-indene]、/>[2',3' -dihydro-spiro [ cyclopentane-1, 1' -indene ]]Or->[1,2,3 a-tetrahydropentalene]。
The term "aryl" as used herein means an aromatic ring in which the atoms forming the ring are each carbon atoms. The aryl ring may be formed from five, six, seven, eight, or more than eight carbon atoms. Aryl groups may be substituted or unsubstituted. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, phenanthryl, and the like.
The term "heteroaryl" refers to an aryl group comprising one or more ring heteroatoms selected from nitrogen, oxygen, sulfur, or a combination thereof, wherein the heteroaryl group has 4 to 10 atoms in its ring system, and provided that the ring of the group does not contain two adjacent nitrogen, oxygen, or sulfur atoms. It is understood that heteroaryl rings may have additional heteroatoms in the ring. In heteroaryl groups having two or more heteroatoms, the two or more heteroatoms may be the same as or different from each other. Heteroaryl groups may be optionally substituted. An N-containing heteroaryl moiety refers to an aryl group in which at least one of the backbone atoms of the ring is a nitrogen atom. Illustrative examples of heteroaryl groups include the following moieties: pyrrole, imidazole, and the like.
The term "halogen" as used herein means fluorine, chlorine, bromine and iodine.
The term "bond", "bonded", "direct bond" or "single bond" as used herein means a chemical bond between two atoms.
The term "moiety" as used herein refers to a particular segment or functional group of a molecule. Chemical moieties are generally considered chemical entities that are embedded in or attached to a molecule.
The term "cyano" or "nitrile" as used herein refers to any organic compound containing a-CN functional group.
The term "ester" refers to a chemical moiety having the formula-COOR, wherein R is alkyl, cycloalkyl, aryl, heteroaryl (bonded through a ring carbon) or heterocycle (bonded through a ring carbon). Any hydroxyl or carboxyl side chain on the compounds described herein may be esterified. The procedure and specific groups for preparing such esters may be any suitable method and can be readily found in the references.
As used herein, the term "ether" refers to a chemical moiety containing an oxygen atom attached to two alkyl or aryl groups, wherein the general formula is R-O-R', wherein the terms alkyl and aryl are as defined herein.
As used herein, the term "ketone" refers to a chemical moiety containing a carbonyl group (carbon-oxygen double bond) attached to two alkyl or aryl groups, wherein the general formula is RC (=o) R', wherein the terms alkyl and aryl are as defined herein.
As used herein, the term "ring-locked" refers to a chemical structure in which one or more series of atoms in a compound are joined to form a ring. The ring size may vary from three to many atoms (e.g., aromatic ring, carbocyclic ring).
The term "BODIPY" as used herein refers to a chemical moiety having the formula:
BODIPY can be prepared from a group consisting of a group of di-substituted boron atoms (usually BF 2 Unit) is composed of a compound dipyrromethene. The IUPAC name of BODIPY is 4, 4-difluoro-4-boron-3 a,4 a-diaza-s-indacene.
The term "naphthalimide" or "naphthalimide derivative" as used herein refers to a chemical moiety having the formula:
the present invention relates to photoluminescent composites that absorb light energy of a first wavelength and emit light energy of a second, higher wavelength. The photoluminescent composite of the present invention comprises an absorption luminescent moiety and an emission luminescent moiety, which are coupled (linked) by a linker (linker) such that their distance is adjusted such that the absorption luminescent moiety transfers its energy to a receptor luminescent moiety, which then emits at a second wavelength that is greater than the absorption first wavelength.
Some embodiments include photoluminescent composites. In some examples, the complex comprises: a blue light absorbing donor chromophore, wherein the donor chromophore comprises a naphthalimideAn amine derivative; ligating the complex; and a ring-locked boron-dipyrromethene (BODIPY) moiety. In some embodiments, the linker complex may covalently link the naphthalimide derivative to the ring-locked BODIPY moiety. In some examples, the naphthalimide derivative absorbs light at a first excitation wavelength and transfers energy to the ring-locked BODIPY moiety, wherein the ring-locked BODIPY moiety then emits light energy at a second wavelength. It is believed that energy transfer from the excited naphthalimide derivative to the ring-locked BODIPY moiety is mediated by fluorescence resonance energy transferResonance Energy Transfer) (FRET) occurs. This view is due to the absorption/emission spectrum of photoluminescent complexes, where there are two main absorption bands, one in the blue (naphthalimide derivative) and one in the ring-locked BODIPY absorption band, and only one emission band is located at the emission wavelength of the BODIPY moiety (see fig. 1 and 2).
In one embodiment, the photoluminescent compound may have a high emission quantum yield. In some embodiments, the emission quantum yield may be greater than 50%, 60%, 70%, 80%, and/or 90%. In many embodiments, the emission quantum yield may be greater than 50%, or 55%, or 60%, or 65%, or 70%, or 75%, or 80%, or 85%, or 90%, or 95%. The emission quantum yield can be measured by dividing the number of emitted photons by the number of absorbed photons, which is equivalent to the emission efficiency of the light emitting portion. In various embodiments, the emission quantum yield of the absorption luminescent moiety may be greater than 80%. In some embodiments, the quantum yield may be greater than 0.8 (80%), 0.81 (81%), 0.82 (82%), 0.83 (83%), 0.84 (84%), 0.85 (85%), 0.86 (86%), 0.87 (87%), 0.88 (88%), 0.89 (89%), 0.9 (90%), 0.91 (91%), 0.92 (92%), 0.93 (93%), 0.94 (94%), 0.95 (95%), 0.96 (96%), 0.97 (97%), 0.98 (98%), and may be as high as approximately 100%. Quantum measurement in the film can be performed by a spectrophotometer, such as a Quantaurus-QY spectrophotometer (Hamamatsu, inc., campbell, calif., USA).
In some embodiments, the photoluminescent compound has an emission band, wherein the emission band can have a full width at half maximum (FWHM) of less than 40 nm. FWHM is the width (in nanometers) of the emission band at an emission intensity that is half the maximum emission intensity of the emission band. In some embodiments, the photoluminescent composite has an emission band FWHM value of less than or equal to about 35nm, less than or equal to about 30nm, less than or equal to about 25nm, or less than or equal to about 20nm. In some embodiments, the FWHM is from about 40nm to about 35nm, from about 35nm to about 30nm, from about 30nm to about 25nm, from about 25nm to about 20nm, or less than about 20nm.
In some embodiments, the photoluminescent compound may have a stokes shift equal to or greater than 45nm. As used herein, the term "stokes shift" means the distance between the excitation peak of the blue light absorbing moiety and the emission peak of the BODIPY moiety. In some embodiments, the stokes shift is at least 45nm. In some embodiments, the stokes shift of the photoluminescent complex may be about 45-50nm, about 50-55nm, about 55-60nm, about 60-65nm, about 65-70nm, about 70-75nm, about 75-80nm, about 80-85nm, about 85-90nm, about 90-95nm, about 95-100nm, or greater than about 100nm, or any number within a range defined by any of these values.
In some embodiments, the maximum peak absorption of the blue light absorbing portion may be between about 400nm and about 480nm wavelength. In some embodiments, the peak absorption wavelength may be between about 400nm to about 405nm, about 405 to 410nm, about 410 to 415nm, about 415 to 420nm, about 420 to 425nm, about 425 to 430nm, about 430 to 435nm, about 435 to 440nm, about 440 to 445nm, about 445 to 450nm, about 450 to 455nm, about 455 to 460nm, about 460 to 465nm, about 465 to 470nm, about 470 to 475nm, about 475 to 480nm, or any wavelength within a range defined by any of these values.
In some embodiments, the blue light absorbing portion may have a red/orange absorption with a maximum peak absorption between about 580nm and about 650nm wavelength. In many embodiments, the peak absorbance may be in the range of about 580 to about 585nm, about 585 to 590nm, about 590 to 595nm, about 595 to 600nm, about 600 to 605nm, about 605 to 610nm, about 610 to 615nm, about 615 to 620nm, about 620 to 625nm, about 625 to 630nm, about 630 to 635nm, about 635 to 640nm, about 640 to 645nm, about 645 to 650nm, or any wavelength within a range defined by any of these values.
In some embodiments, the emission peak of the photoluminescent complex can be between about 590nm to about 660 nm. In many embodiments, the emission peak may be between about 590nm and about 595nm, about 595-600nm, about 600-605nm, about 605-610nm, about 610-615nm, about 615-620nm, about 620-625nm, about 625-630nm, about 630-635nm, about 635-640nm, about 640-645nm, about 645-650nm, about 650-655nm, about 655-660nm, or any wavelength within a range defined by any of these values.
Other embodiments include photoluminescent complexes in which the spatial distance of the blue light absorbing naphthalimide derivative and the BODIPY moiety is modulated by linking the complex to improve transfer of energy of the blue light absorbing naphthalimide derivative to the BODIPY moiety.
A photoluminescent complex (PLC) is described comprising a naphthalimide derivative that absorbs blue light, a linking complex, and a ring-locked BODIPY moiety. The linking complex covalently links the blue light absorbing naphthalimide derivative to the ring-locked BODIPY moiety. In some embodiments, the naphthalimide derivative absorbs light energy at a first excitation wavelength and transfers energy to a ring-locked BODIPY moiety, wherein the ring-locked BODIPY moiety absorbs energy from the naphthalimide derivative and emits light energy at a second, higher wavelength. In such an embodiment, the photoluminescent compound has an emission quantum yield greater than 80%.
The linking complex covalently links the blue light absorbing naphthalimide derivative to the ring-locked BODIPY moiety. The linking complex can be tuned to adjust the spatial distance between the blue light absorbing naphthalimide derivative and the ring-locked BODIPY moiety. Quantum yields can be tuned by adjusting the spatial distance between the ring-locked naphthalimide derivative and the ring-locked BODIPY. In some embodiments, the blue light absorbing naphthalene dicarboxylic acid is isolated The imine derivative may be about a distance from the ring-locked BODIPY moietyThe following is given. The linking complex can maintain the distance between the blue light absorbing naphthalimide derivative and the ring-locked BODIPY moiety.
In some embodiments, the photoluminescent complex comprises a linking complex (L), wherein the linking complex covalently links the blue light absorbing naphthalimide derivative to the ring-locked BODIPY moiety. In some embodiments, the linking complex may comprise a single bond between the naphthalimide derivative and the ring-locked BODIPY moiety.
In some embodiments, the linking complex may comprise an unsubstituted ester, a substituted ester, an unsubstituted ether, or a substituted ether. In some embodiments, the linking complex may comprise optionally substituted C 2-7 An ester group.
Some examples include a linking complex comprising a substituted ester group, wherein the linking complex may be selected from one of the following structures:
in some embodiments, the linking complex may comprise an unsubstituted ester group. When the linking complex comprises an unsubstituted ester group, the linking complex comprises one of the following structures:
in some embodiments, the linking complex may comprise an unsubstituted ether and/or a substituted ether. When the linking complex comprises an unsubstituted ether and/or a substituted ether, the linking complex comprises one of the following structures:
Photoluminescent complexes of the invention may comprise ring-locked BODIPY moieties. The ring-locked BODIPY moiety may have the general formula:
in some embodiments, R 1 And R is 2 May be H, or C 1-3 An alkyl group. In some embodiments, R 1 And R is 2 May be a substituted aryl moiety, wherein the substituents on the aryl moiety may be C 1-6 An alkyl group. In some embodiments, R 3 And R is 4 Can be H, F, br, or-CF 3 . In some embodiments, R 5 And R is 6 Can be H, halogen (such as-F, -Cl and/or-Br), C 1 -C 3 Alkyl (e.g. -CH 3 )、C 1 -C 3 Alkoxy (e.g. -OCH 3 ). In some embodiments, X may be C 1 -C 3 Alkyl radicals, e.g. -CH 2 -；-CH 2 CH 2 -、-CH 2 CH 2 CH 2 -, or spirocycloalkyl.
In some embodiments, R 1 H.
In some embodiments, R 1 Is C 1-3 An alkyl group.
In some embodiments, R 2 H.
In some embodiments, R 2 Is C 1-3 An alkyl group.
In some embodiments, R 1 And R is 2 H.
In some embodiments, R 1 And R is 2 Is C 1-3 An alkyl group.
In some embodiments, R 1 Is a substituted aryl moiety, such as phenyl, wherein the substituent on the aryl moiety (e.g., phenyl) may be C 1-6 An alkyl group.
In some embodiments, R 2 Is a substituted aryl moiety, e.g. phenyl, wherein aryl is The substituents on the base moiety (e.g. phenyl) may be C 1-6 An alkyl group.
In some embodiments, R 1 And R is 2 Is a substituted aryl moiety, such as phenyl, wherein the substituent on the aryl moiety (e.g., phenyl) may be C 1-6 An alkyl group.
In some embodiments, R 3 H.
In some embodiments, R 3 F.
In some embodiments, R 3 Is Br.
In some embodiments, R 3 is-CF 3 。
In some embodiments, R 4 H.
In some embodiments, R 4 F.
In some embodiments, R 4 Is Br.
In some embodiments, R 4 is-CF 3 。
In some embodiments, R 3 And R is 4 H.
In some embodiments, R 3 And R is 4 F.
In some embodiments, R 3 And R is 4 Is Br.
In some embodiments, R 3 And R is 4 is-CF 3 。.
In some embodiments, R 5 H.
In some embodiments, R 5 is-F.
In some embodiments, R 5 is-Cl.
In some embodiments, R 5 is-Br.
In some embodiments, R 5 Is C 1 -C 3 An alkyl group.
In some embodiments, R 5 is-CH 3 。
In some embodiments, R 5 Is C 1 -C 3 An alkoxy group.
In some embodiments, R 5 is-OCH 3 。
In some embodiments, R 6 H.
In some embodiments, R 6 is-F.
In some embodiments, R 6 is-Cl.
In some embodiments, R 6 is-Br.
In some embodiments, R 6 Is C 1 -C 3 An alkyl group.
In some embodiments, R 6 is-CH 3 。
In some embodiments, R 6 Is C 1 -C 3 An alkoxy group.
In some embodiments, R 6 is-OCH 3 。
In some embodiments, R 5 And R is 6 H.
In some embodiments, R 5 And R is 6 is-F.
In some embodiments, R 5 And R is 6 is-Cl.
In some embodiments, R 5 And R is 6 is-Br.
In some embodiments, R 5 And R is 6 Is C 1 -C 3 An alkyl group.
In some embodiments, R 5 And R is 6 is-CH 3 。
In some embodiments, R 5 And R is 6 Is C 1 -C 3 An alkoxy group.
In some embodiments, R 5 And R is 6 is-OCH 3 。
In some embodiments, R 5 And R is 6 Can be H, -CH 3 Cl, F, or OCH 3 。
In some embodiments, X is C 1 -C 3 An alkyl group.
In some embodiments, X is-CH 2 。
In some embodiments, X is-CH 2 CH 2 -。
In some embodiments, X is-CH 2 CH 2 CH 2 -。
In some embodiments, X is spirocycloalkyl.
In some embodiments, L is an unsubstituted ester.
In some embodiments, L is a substituted ester.
In some embodiments, L is an unsubstituted ether.
In some embodiments, L is a substituted ether.
Many embodiments include a blue light absorbing naphthalimide derivative (Z), wherein the blue light absorbing naphthalimide derivative may have the general formula:
wherein Y may be oxygen (O) or sulfur (S). In some embodiments, R 7 And/or R 8 Can be hydrogen (H), substituted or unsubstituted aryl, or-CF 3 . In some embodiments, R 9 May be H, substituted or unsubstituted aryl, C 1-5 Alkylaryl, substituted or unsubstituted aryl carboxylic acids (e.g. p-CO 2 -t-Bu-phenyl), or R 9 Without substitution.
In some embodiments, Y is oxygen (O).
In some embodiments, Y is sulfur (S).
In some embodiments, R 7 H.
In some embodiments, R 7 Is a substituted aryl group.
In some embodiments, R 7 Is an unsubstituted aryl group.
In some embodiments, R 7 is-CF 3 。
In some embodiments, R 8 H.
In some embodiments, R 8 Is a substituted aryl group.
In some embodiments, R 8 Is an unsubstituted aryl group.
In some embodiments, R 8 is-CF 3 。
In some embodiments, R 7 And R is 8 H.
In some embodiments, R 7 And R is 8 Is a substituted aryl group.
In some embodiments, R 7 And R is 8 Is an unsubstituted aryl group.
In some embodiments, R 7 And R is 8 is-CF 3 。
In some embodiments, R 9 H.
In some embodiments, R 9 Is a substituted aryl group.
In some embodiments, R 9 Is an unsubstituted aryl group.
In some embodiments, R 9 Is C 1-5 Alkylaryl groups.
In some embodiments, R 9 Is a substituted aryl carboxylic acid.
In some embodiments, R 9 Is an unsubstituted aryl carboxylic acid.
In some embodiments, R 9 Is p-CO 2 -t-Bu-phenyl.
The photoluminescent composite of the present invention may be represented by the following structure, which is provided for illustrative purposes only and should in no way be construed as limiting:
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or a combination thereof.
In some embodiments, the photoluminescent complex comprises a naphthalimide derivative that absorbs blue light. In some examples, the blue light absorbing naphthalimide derivative may comprise an organic luminophore. In many embodiments, the maximum peak absorption of the blue light absorbing portion may be between about 400nm and about 480nm wavelength. In some embodiments, the peak absorption may be at least about 400nm, 410nm, 420nm, 430nm, 440nm, 450nm, or 460nm. In some embodiments, the peak absorption may be less than about 410nm, 420nm, 430nm, 440nm, 450nm, and 460nm, 470nm, or 480nm. In many embodiments, the maximum absorbance peak of the photoluminescent complex can be about 450nm. In some embodiments, the maximum absorbance peak of the blue light absorbing naphthalimide derivative may be about 410nm and the minimum maximum absorbance peak may be about 400nm. However, in many embodiments, the peak absorbance maximum of the blue light absorbing naphthalimide derivative may be about 480nm.
Some embodiments include a color conversion film, wherein the color conversion film includes: a color conversion layer, wherein the color conversion layer comprises a resin matrix and the above-described photoluminescent composite dispersed within the resin matrix. In many embodiments, the color conversion film can include one or more photoluminescent composites described herein.
Some embodiments include a color conversion film that may be about 1 μm to about 200 μm thick. In many embodiments, the color conversion film can be described as about 1 μm to about 5 μm thick, about 5 μm to about 10 μm thick, about 10 μm to about 15 μm thick, about 15 μm to about 20 μm thick, about 20 μm to about 40 μm thick, about 40 μm to about 80 μm thick, about 80 μm to about 120 μm thick, about 120 μm to about 160 μm thick, about 160 μm to about 200 μm thick, or any thickness defined by the above ranges.
In some embodiments, the color conversion film may absorb light in a wavelength range of about 400nm to about 480nm, and may emit light in a range of about 590nm to about 660 nm.
In some embodiments, the color conversion film may further include a transparent substrate layer. The transparent substrate layer has two opposing surfaces, wherein the color conversion layer may be disposed on and in physical contact with a surface of the transparent layer that is to be adjacent to the light emitting source. The transparent substrate is not particularly limited, and one skilled in the art will be able to select a transparent substrate from those used in the art. Some non-limiting examples of transparent substrates include PE (polyethylene), PP (polypropylene), PEN (polyethylene naphthalate), PC (polycarbonate), PMA (polymethyl acrylate), PMMA (polymethyl methacrylate), CAB (cellulose acetate butyrate), PVC (polyvinyl chloride), PET (polyethylene terephthalate), PETG (glycol modified polyethylene terephthalate), PDMS (polydimethylsiloxane), COC (cyclic olefin copolymer), PGA (polyglycolide or polyglycolic acid), PLA (polylactic acid), PCL (polycaprolactone), PEA (polyethylene adipate), PHA (polyhydroxyalkanoate), PHBV (poly (3-hydroxybutyrate-co-3-hydroxyvalerate)), PBE (polybutylene terephthalate), PTT (polytrimethylene terephthalate). Any of the above resins may be the corresponding monomers and/or polymers.
In some embodiments, the transparent substrate may have two opposing surfaces. In many embodiments, the color conversion film may be disposed on one of the opposing surfaces and disposed in physical contact with that surface. In some embodiments, the side of the transparent substrate on which the color conversion film is not disposed may be adjacent to the light source. The substrate may act as a support during the preparation of the material of the color conversion film. The kind of the substrate used is not particularly limited, and the material and/or thickness is not limited as long as it is transparent and can function as a support. One skilled in the art can determine which material and thickness to use as a support substrate.
Some embodiments include a method of preparing a color conversion film, wherein the method comprises: dissolving a photoluminescent compound described herein and a binder resin in a solvent; and applying the mixture to a surface of a transparent substrate.
Binder resins that may be used with the photoluminescent compound include resins such AS acrylic resins, polycarbonate resins, ethylene-vinyl alcohol copolymer resins, ethylene-vinyl acetate copolymer resins and their saponification products, AS resins, polyester resins, vinyl chloride-vinyl acetate copolymer resins, polyvinyl butyral resins, polyvinyl phosphonic acid (PVPA), polystyrene resins, phenolic resins, phenoxy resins, polysulfones, nylons, cellulose resins, and cellulose acetate resins. In some embodiments, the binder resin may be a polyester resin and/or an acrylic resin.
Solvents that may be used to dissolve or disperse the composite and resin may includeAlkanes such as butane, pentane, hexane, heptane and octane; cycloalkanes such as cyclopentane, cyclohexane, cycloheptane, and cyclooctane; alcohols such as ethanol, propanol, butanol, pentanol, hexanol, heptanol, octanol, decanol, undecanol, diacetone alcohol and furfuryl alcohol; cellosolve (cellosolve) TM ) Such as methyl cellosolve (Methyl Cellosolve) TM ) Ethyl Cellosolve (Ethyl Cellosolve) TM ) Butyl Cellosolve (Butyl Cellosolve) TM ) Methyl cellosolve (methyl cellosolve) TM ) Acetate and Ethyl Cellosolve (Ethyl Cellosolve) TM ) An acetate ester; propylene glycol and its derivatives such as propylene glycol monomethyl ether, propylene glycol monoethyl ether acetate, propylene glycol monobutyl ether acetate, and dipropylene glycol dimethyl ether; ketones such as acetone, methyl amyl ketone, cyclohexanone and acetophenone; ethers such as dioxane and tetrahydrofuran; esters such as butyl acetate, amyl acetate, ethyl butyrate, butyl butyrate, diethyl oxalate, ethyl pyruvate, ethyl 2-hydroxybutyrate, ethyl acetoacetate, methyl lactate, ethyl lactate and methyl 3-methoxypropionate; halogenated hydrocarbons such as chloroform, methyl chloride and tetrachloroethane; aromatic hydrocarbons such as benzene, toluene, xylene and cresol; and highly polar solvents such as dimethylformamide, dimethylacetamide and N-methylpyrrolidone.
Some embodiments include a backlight unit. In some examples, the backlight unit may include the aforementioned color conversion film comprising the photoluminescent compound described herein.
Other embodiments may include a display device, wherein the device may include a backlight unit as described herein.
Unless otherwise indicated, all numbers expressing quantities of ingredients, properties such as molecular weight, reaction conditions, and so forth used in the specification and embodiments are to be understood as being modified in all instances by the term "about". Accordingly, unless specified to the contrary, the numerical parameters set forth in the specification and attached embodiments are approximations that may vary depending upon the desired properties sought to be obtained. At the very least, and not as an attempt to limit the application of the doctrine of equivalents to the scope of the embodiments, each numerical parameter should at least be construed in light of the number of reported significant digits and by applying ordinary rounding techniques.
For the disclosed processes and/or methods, the functions performed in the processes and methods may be implemented in a different order, as indicated above and below. Furthermore, the outlined steps and operations are provided as examples only, and some of the steps and operations may be optional, combined into fewer steps and operations, or extended to additional steps and operations.
The invention may sometimes be illustrated as a different component contained within or connected to a different other component. The architecture of this description is merely an example, and many other architectures can be implemented to achieve the same or similar functionality.
The terms (e.g., bodies of the appended embodiments) used in this disclosure and in the appended embodiments are generally intended as "open" terms (e.g., the term "including" should be interpreted as "including but not limited to," the term "having" should be interpreted as "having at least," the term "comprising" should be interpreted as "including but not limited to," etc.). In addition, if a specific number of an element is introduced, this can be interpreted to mean at least the recited number, as indicated above and below (e.g., a simple recitation of "two recitations" without other modifiers means at least two recitations or two or more recitations). As used herein, any disjunctive word and/or phrase presenting two or more alternative terms should be understood to contemplate the possibilities of including one of the terms, either of the terms, or both terms. For example, the phrase "a or B" will be understood to include the possibilities of "a" or "B" or "a and B". Similarly, the phrase "a and/or B" will be understood to include the possibilities of "a" or "B" or "a and B".
The terms "a" and "an" and "the" and similar referents used in the context of describing the invention (especially in the context of the following embodiments) are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context. The use of any and all examples, or exemplary language (e.g., "such as" or "e.g.," such as ") provided herein, is intended merely to better illuminate the invention and does not pose a limitation on the scope of any embodiment. No language in the specification should be construed as indicating any non-claimed element as essential to the practice of the invention.
The grouping of alternative elements or embodiments disclosed herein should not be construed as limiting. Each group member may be referred to and presented individually or in any combination with other members of the group or other elements found herein. For convenience and/or patentability reasons, it is contemplated that one or more members of a group may be included in or deleted from the group. When any such inclusion or deletion occurs, the specification is considered to contain the modified group, thereby satisfying the written description of all markush groups used in the appended embodiments.
Certain embodiments are described herein, including the best mode known to the inventors for carrying out the invention. Of course, variations of those described embodiments may become apparent to those of ordinary skill in the art upon reading the foregoing description. The inventors expect skilled artisans to employ such variations as appropriate, and the inventors intend for the invention to be practiced otherwise than as specifically described herein. Accordingly, embodiments are allowed by applicable law. Moreover, any combination of the above-described elements in all possible variations thereof is contemplated unless otherwise indicated herein or clearly contradicted by context. Finally, it should be understood that the embodiments disclosed herein illustrate the principles of the embodiments. Thus, by way of example, and not limitation, alternative embodiments may be utilized in accordance with the teachings herein. Hereinafter, the embodiments are not limited to the embodiments precisely shown and described herein.
Embodiments are described below:
embodiment 1.
A photoluminescent compound comprising:
a blue light absorbing donor chromophore, wherein the donor chromophore comprises a naphthalimide derivative;
ligating the complex; and
a ring-locked boron-dipyrromethene (BODIPY) moiety;
Wherein the linking complex covalently links the donor chromophore with the naphthalimide derivative and the ring-locked BODIPY moiety, wherein the naphthalimide derivative absorbs blue light energy at a first excitation wavelength and transfers energy to the ring-locked BODIPY moiety, wherein the ring-locked BODIPY moiety absorbs energy from the naphthalimide derivative and emits light energy at a second, higher wavelength, and wherein the photoluminescence complex has an emission quantum yield greater than 80%.
Embodiment 2.
The photoluminescent complex according to embodiment 1, wherein the naphthalimide derivative of the donor chromophore has the following general formula:
wherein Y is selected from oxygen (O) or sulfur (S); wherein R is 7 And R is 8 Independently selected from hydrogen (H), substituted or unsubstituted aryl, or-CF 3 The method comprises the steps of carrying out a first treatment on the surface of the And wherein R is 9 Independently selected from hydrogen (H), substituted or unsubstituted aryl, C 1 -C 5 Alkyl, or R 9 Without substitution.
Embodiment 3.
The photoluminescent complex according to embodiment 1, wherein the ring-locked BODIPY moiety has the following general formula:
wherein R is 1 And R is 2 Independently selected from H, or C 1 -C 3 An alkyl group; wherein R is 3 And R is 4 Independently selected from H, F, br, -CF 3 Or a bond to L-Z; wherein R is 5 And R is 6 Independently selected from H, C 1 -C 3 Alkyl, halogen, or C 1 -C 3 An alkoxy group; and wherein X is independently selected from C 1 -C 3 Alkyl, -CH 2 CH 2 -、-CH 2 CH 2 CH 2 -, or spiro-cycloalkyl.
Embodiment 4.
The photoluminescent complex according to embodiment 3, wherein L is a linking complex, which may be a substituted ester, an unsubstituted ester, a substituted ether, or an unsubstituted ether.
Embodiment 5.
The photoluminescent complex according to embodiment 3, wherein Z is a donor chromophore comprising a naphthalimide derivative.
Embodiment 6.
The photoluminescent complex of embodiment 1 or 4, wherein the linking complex is an unsubstituted ester; wherein the unsubstituted ester comprises one of the following structures:
embodiment 7.
The photoluminescent complex of embodiment 1 or 4, wherein the linking complex is a substituted ester; wherein the substituted ester comprises one of the following structures:
embodiment 8.
The photoluminescent complex of embodiment 1 or 4, wherein the linking complex is an unsubstituted ether and/or a substituted ether; wherein the unsubstituted ether and/or substituted ether comprises one of the following structures:
embodiment 9.
The photoluminescent compound of embodiment 1, 2, 3, 4, 5, 6, 7, or 8 wherein the photoluminescent compound comprises one of the following structures:
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Or they areAnd (5) combining.
Embodiment 10.
A color conversion film, comprising:
a transparent substrate layer;
a color conversion layer, wherein the color conversion layer comprises a resin matrix; and
at least one photoluminescent composite, wherein the at least one photoluminescent composite comprises the photoluminescent composite of embodiment 1, 2, 3, 4, 5, 6, 7, 8, or 9 dispersed in the resin matrix.
Embodiment 11.
The color conversion film of embodiment 10, further comprising a singlet oxygen quencher.
Embodiment 12.
The color conversion film of embodiment 10, further comprising a radical scavenger.
Embodiment 13.
The color conversion film of embodiment 10, wherein the film has a thickness between 10 μιη to 200 μιη.
Embodiment 14.
The color conversion film of embodiment 10, wherein the film absorbs light in a wavelength range of about 400nm to about 480nm and emits light in a wavelength range of about 590nm to about 660 nm.
Embodiment 15.
A method of making the color conversion film of embodiment 10, 11, 12, 13, or 14, the method comprising:
dissolving the photoluminescent composite as described in embodiments 1, 2, 3, 4, 5, 6, 7, 8, or 9 and a binder resin in a solvent; and
The mixture is applied to one of the opposing surfaces of the transparent substrate.
Embodiment 16.
A backlight unit comprising the color conversion film of embodiment 10, 11, 12, 13, or 14.
Embodiment 17.
A display device comprising the backlight unit according to embodiment 16.
Examples
It has been found that embodiments of the photoluminescent complexes described herein have improved performance compared to other forms of dyes used in color conversion films. These benefits are further demonstrated by the following examples, which are intended to illustrate the invention, but are not intended to limit the scope or rationale in any way.
The following examples are synthetic procedures for many embodiments of naphthalimide derivatives (i.e., blue absorber intermediates) as described herein:
example 1 (Ex-1):
ex-1.1: a mixture of 2-nitrophenol (6.6 g,48 mmol), KOH powder (2.4 g,43 mmol) was mixed and stirred under vacuum for 30 minutes, then copper powder (0.4 g) was added followed by 100mL of anhydrous DMF. The mixture was stirred for 5 minutes, then 4-chloronaphthalene dicarboxylic anhydride (5.1 g,22 mmol) was added. The whole was degassed and then heated under reflux for 1.5 hours. After cooling to room temperature, 100mL of 20% hydrochloric acid was added dropwise to the resultant reaction mixture, which was allowed to stand for 2 hours. The precipitate was collected by filtration and then dried overnight under vacuum to give a yellowish brown solid (4.6 g). Further purification was performed by stirring in refluxing acetic acid (50 mL) for 1 hour, and then cooled to room temperature. Filtration and drying in air gave a yellow solid (3.0 g, 41% yield). Confirmation by LCMS (APCI): c (C) 18 H 10 NO 6 Calculated value of (m+h): 336.0; actual measurement value: 336. 1 h NMR (400 MHz, chloroform-d) δ8.80 (dd, j=8.5, 1.2hz, 1H), 8.72 (dd, j=7.3, 1.2hz, 1H), 8.50 (d, j=8.2 hz, 1H), 8.19 (dd, j=8.2, 1.7hz, 1H), 7.90 (dd, j=8.5, 7.3hz, 1H), 7.79 (td, j=7.9, 1.7hz, 1H), 7.54 (td, j=8.0, 1.3hz, 1H), 7.39 (dd, j=8.3, 1.2hz, 1H), 6.89 (d, j=8.2 hz, 1H).
Ex-1.2: 4- (2-Nitrophenoxy) -1, 8-naphthalic anhydride (2.0 g,6 mmol) andiron powder [ (iron powder)<A mixture of 10 μm,0.91g,16 mmol) in acetic acid (75 mL) was heated at reflux for 30 min. The resulting solution was poured into water (220 mL). The resulting precipitate was collected by filtration, then washed with water and dried well in air, then placed under vacuum to give a yellow solid (1.65 g, 90% yield). Confirmation by LCMS (APCI): c (C) 18 H 12 NO 4 Calculated value of (m+h): 306.1; actual measurement value: 306.
ex-1.3: the compound 4- (2-aminophenoxy) -1, 8-naphthalenedicarboxylic anhydride (1.5 g,4.9 mmol) was dispersed in acetic acid (35 mL) and cooled to 0 ℃. While stirring, pre-chilled hydrochloric acid (3 mL,37 mmol) was added followed by dropwise addition of a solution of sodium nitrite (3.29 g,46 mmol) in 12mL of water at 0deg.C. The whole was stirred at 0 ℃ for 1 hour, then transferred to an addition funnel, and a refluxing copper sulfate solution (5.08 g,20mmol, in 50mL of water) was added dropwise over 1 hour. After cooling to room temperature, the precipitate was collected by filtration, washed with water and acetone, then dried in air, and then dried in vacuo to give a yellow solid (0.92 g, 65% yield). Confirmation by LCMS (APCI): c (C) 18 H 8 O 4 Calculated value of (M-): 288.0; actual measurement value: 288. 1 h NMR (400 MHz, chloroform-d) δ8.61 (dd, j=17.1, 8.1hz, 2H), 8.09 (d, j=8.0 hz, 1H), 7.97 (d, j=7.9 hz, 1H), 7.59 (t, j=7.7 hz, 1H), 7.40 (t, j=8.1 hz, 2H), 7.33 (d, j=8.4 hz, 1H).
Ex-1: 1H, 3H-Isochromo [6,5,4-mna ]]A mixture of xanthene-1, 3-dione (100 mg,0.347 mmol), 2- (4-aminophenyl) acetic acid (135 mg,0.9 mmol) in 5mL of DMF was heated in a microwave reactor at 165℃for 2 hours. After cooling to 50 ℃, 1.5mL of acetone was added dropwise to the resulting solution to form a yellow precipitate, which was collected by filtration and washed with acetone, and dried in air to give a yellow solid (88 mg, yield 61%). Confirmation by LCMS (APCI): c (C) 26 H 15 NO 5 Calculated value of (M-): 421.1; actual measurement value: 421. 1 H NMR(400MHz,DMSO-d 6 )δ8.27(d,J＝45.1Hz,4H),7.67-7.00(m,8H),3.58(s,2H)。
example 2 (Ex-2):
ex-2: 1H, 3H-Isochromo [6,5,4-mna ]]A mixture of xanthene-1, 3-dione (100 mg,0.347 mmol), 4- (4-aminophenyl) butyric acid (125 mg,0.7 mmol) in 5mL of DMF was heated in a microwave reactor at 165℃for 2.5 hours. To the mixture was added 15mL of acetone, and the resulting precipitate was collected by filtration and dried in air, followed by drying in a vacuum oven at 100 ℃ for 1 hour to give a yellow solid (120 mg, yield 77%). Confirmation by LCMS (APCI): c (C) 28 H 19 NO 5 Calculated value of (M-): 449.1; actual measurement value: 449. 1 H NMR(400MHz,DMSO-d 6 )δ8.38(d,J＝41.6Hz,4H),7.81-6.97(m,8H),2.69-2.64(m,2H),2.26(t,J＝7.2Hz,2H),1.87(p,J＝7.2Hz,2H)。
example 3 (Ex-3):
ex-3.1: to a mixture of compound EX-1.3 (290 mg,1.0 mmol) in o-dichlorobenzene (30 mL) was added bromine (1.98 g,12 mmol). The mixture was heated at 75 ℃ for 30 hours. After cooling to room temperature, the solid was collected by filtration and dried in air to give 290mg of a yellow solid as the desired product. The filtrate was loaded on silica gel and purified by flash chromatography using an eluent of hexane/dichloromethane (50% →100% dichloromethane). The desired fractions were collected and the solvent was removed to yield 110mg of a yellow solid. 400mg of total product were obtained in 89.7% yield. LCMS (APCI-): c (C) 18 H 6 Br 2 O 4 Is calculated by the following steps: 443.9; found 444. 1 H NMR(400MHz,d 2 -TCE)δ9.40(dd,J＝8.5,1.5Hz,1H),8.71(s,1H),8.67(s,1H),7.60(ddd,J＝8.4,7.1,1.5Hz,1H),7.48(dd,J＝8.3,1.4Hz,1H),7.38(ddd,J＝8.5,7.1,1.4Hz,1H)。
Ex-3.2: compound EX-3.1 (190 mg,0.426 mmol) 4- (4-aminophenyl) butanoic acidA mixture of (180 mg,0.64 mmol) 4- (N, N-dimethylamino) -pyridine (4 mg) in anhydrous N, N-Dimethylformamide (DMF) (4 mL) was heated at 165℃for 2.5 h. After the mixture was cooled to room temperature and left to stand overnight, the solid was collected by filtration, washed with acetone and dried in a vacuum oven at 90 ℃ for 1 hour to give a yellow solid (220 mg, 84.5% yield). LCMS (APCI-): c (C) 28 H 17 Br 2 NO 5 Is calculated by the following steps: 604.95; actual measurement value: 605. 1 H NMR(400MHz,DMSO-d 6 )δ9.42(dd,J＝8.6,1.5Hz,1H),8.57(d,J＝4.6Hz,2H),7.83-7.68(m,1H),7.63-7.44(m,2H),7.34(d,J＝8.3Hz,2H),7.31-7.16(m,2H),2.67(dd,J＝4.8,2.8Hz,2H),2.28(t,J＝7.4Hz,2H),1.95-1.80(m,2H)。
ex-3: a mixture of compound EX-3.2 (100 mg,0.165 mmol), (3, 5-bis (trifluoromethyl) phenyl) boronic acid (170 mg,0.66 mmol), pd (dppf) Cl2 (20 mg,0.027 mmol) and potassium carbonate (138 mg,1 mmol) in THF/water (5 mL/0.5 mL) was degassed and then heated at 80℃for 2 hours. After cooling to room temperature, the precipitate was collected by filtration, washed with acetone and then dried in a vacuum oven at 90 ℃ for 2 hours. Obtained as a yellow solid (142 mg, 94% yield). LCMS (APCI-): c (C) 44 H 23 F 12 NO 5 Is calculated by the following steps: 873.14; actual measurement value: 873. 1 H NMR(400MHz,d 2 -TCE)δ8.65(s,1H),8.40(s,1H),8.17(s,2H),7.96(d,J＝19.3Hz,4H),7.38(d,J＝8.4Hz,1H),7.33(d,J＝8.0Hz,2H),7.18(d,J＝8.0Hz,3H),6.90(d,J＝6.3Hz,2H),2.72(t,J＝7.6Hz,2H),2.38(t,J＝7.4Hz,2H),2.03-1.93(m,2H)。
example 4 (Ex-4):
ex-4.1: a mixture of 4-bromo-1, 8-naphthalic anhydride (2.77 g,10 mmol), 4-bromo-2-nitrophenol (3.27 g,15 mmol) was degassed under vacuum for 30 minutes, then anhydrous NMP (50 mL) was added followed by sodium hydroxide (0.2 g,5 mmol) and copper powder (0.318 g,5 mmol). The mixture was bubbled with argon for 20 minutes and then under argon atmosphereHeated at 180℃overnight. After the mixture was cooled to room temperature, 50mL of 20% aqueous hydrochloric acid solution was added dropwise to the solution, followed by 50mL of water. The resulting mixture was allowed to stand for 3 hours, then filtered to collect precipitate, which was dried in vacuo to give 4.6g of crude product. The crude product was dispersed in 30mL of acetone and stirred overnight at room temperature to dissolve impurities. Filtration and drying in vacuo gave a tan solid as the desired product (3.3 g, 80% yield). LCMS (apci+): c (C) 18 H 9 BrNO 6 Calculated value of (m+h) = 413.95; actual measurement value: 414. 1 H NMR(400MHz,TCE-d2)δ8.70(dd,J＝8.4,1.2Hz,1H),8.63(dd,J＝7.3,1.2Hz,1H),8.41(d,J＝8.3Hz,1H),8.24(d,J＝2.4Hz,1H),7.89-7.79(m,2H),7.20(d,J＝8.7Hz,1H),6.82(d,J＝8.3Hz,1H)。
ex-4.2: a mixture of compound EX-4.1 (1.5 g,3.6 mmol), iron powder (0.60 g,10.8 mmol) in acetic acid (50 mL) was heated at 125℃for 30 min. After cooling to room temperature, 100mL of water was added to the mixture while stirring. The resulting mixture was filtered and washed with water, and dried under air and vacuum to give a solid (1.35 g, 82% yield). LCMS (APCI-): c (C) 18 H 10 BrNO 4 Calculated value of = 382.98; actual measurement value: 383. 1 H NMR(400MHz,DMSO-d 6 )δ9.01-8.26(m,3H),7.96(s,1H),6.93(dd,J＝85.2,36.5Hz,4H),5.54(s,2H)。
ex-4.3: compound EX-4.2 (2.65 g,6.9 mmol) is dispersed in acetic acid (50 mL)/water (10 mL) and cooled to 0deg.C. While stirring, pre-chilled hydrochloric acid (2.8 mL,34.5 mmol) was added followed by dropwise addition of a solution of sodium nitrite (3.57 g,52 mmol) in 15mL of water at 0deg.C. The whole was stirred at 0 ℃ for 1 hour, then transferred to an addition funnel, and copper sulfate solution (12 g,47mmol in 140mL of water) was added dropwise over 1 hour at 130 ℃. After cooling to room temperature, the precipitate was collected by filtration, washed with water (100 ml×3), and then stirred in 50mL of acetone at 40 ℃ for 30 minutes. Filtration, drying in air, and then drying in vacuo gave a tan solid (1.76 g, 70% yield). LCMS (apci+): c (C) 18 H 8 BrO 4 (M+H)Calculated = 366.95; actual measurement value: 367. 1 H NMR(400MHz,d2-TCE)δ8.51(dd,J＝12.3,8.1Hz,2H),8.12(d,J＝2.3Hz,1H),7.86(d,J＝7.9Hz,1H),7.60(dd,J＝8.8,2.3Hz,1H),7.28(d,J＝8.3Hz,1H),7.23(d,J＝8.8Hz,1H)。
ex-4.4: a mixture of compound EX-4.3 (550 mg,1.5 mmol), 4- (4-aminophenyl) butanoic acid (537 mg,3 mmol) and DMAP (12.2 mg,0.1 mmol) in 10mL of DMF was heated in a microwave reactor at 165℃for 2.5 hours. The resulting solution was dropped into 50mL of acetone while stirring. A precipitate formed, was filtered and dried in a vacuum oven at 60 ℃ overnight to give the desired product as a tan solid (0.49 g, 62% yield). LCMS (APCI-): c (C) 28 H 18 BrNO 5 Calculated value of = 527.04; actual measurement value: 527. 1 H NMR(400MHz,DMSO-d 6 )δ8.54(d,J＝2.3Hz,1H),8.41(dd,J＝9.9,8.0Hz,2H),8.33(d,J＝7.9Hz,1H),7.71(dd,J＝8.8,2.3Hz,1H),7.39(dd,J＝8.6,4.2Hz,2H),7.25(d,J＝8.0Hz,2H),7.17(d,J＝7.9Hz,2H),2.63-2.55(m,2H),2.27-2.15(m,2H),1.87-1.73(m,2H)。
ex-4: compound EX-4.4 (385 mg,0.729 mmol), phenylboronic acid (178 mg,1.45 mmol), pd (dppf) Cl 2 (36 mg,0.05 mmol), potassium carbonate (276 mg,2 mmol) in THF/DMF/water (20L/4 mL/2 mL) and then heated at 80℃overnight. The mixture was treated with 200mL of ethyl acetate and 50mL of 0.6N aqueous hydrochloric acid. The aqueous phase was extracted with ethyl acetate (100 mL. Times.2). The organic phase was collected and washed with brine (100 ml×2), dried over sodium sulfate, then dried loaded on silica gel, and purified by flash chromatography using an eluent of DCM/EA (0% to 40% EA with 0.1% tfa). The main desired fraction was collected and the solvent was removed under reduced pressure to give a yellow solid (250 mg, 65% yield). LCMS (APCI-): c (C) 34 H 23 NO 5 Calculated value of = 525.16; actual measurement value: 525. 1 H NMR(400MHz,TCE-d 2 )δ8.55(dd,J＝19.5,8.1Hz,2H),8.20(d,J＝2.1Hz,1H),8.01(d,J＝8.1Hz,1H),7.72(dd,J＝8.6,2.1Hz,1H),7.62(d,J＝7.3Hz,2H),7.51-7.28(m,7H),7.17(d,J＝8.2Hz,2H),2.72(t,J＝7.7Hz,2H),2.39(t,J＝7.3Hz,2H),1.99(q,J＝7.2Hz,2H)。
example 5 (Ex-5)
Ex-5: compound EX-4.4 (385 mg,0.729 mmol), 3, 5-bis- (trifluoromethyl) phenylboronic acid (374 mg,1.45 mmol), pd (dppf) Cl 2 (36 mg,0.05 mmol), potassium carbonate (276 mg,2 mmol) in a cosolvent of THF/DMF/water (20L/4 mL/2 mL) and then heated overnight at 80 ℃. The mixture was treated with 200mL of ethyl acetate and 50mL of 0.6N aqueous hydrochloric acid. The aqueous phase was extracted with ethyl acetate (100 mL. Times.2). The organic phase was collected and washed with brine (100 ml×2), dried over sodium sulfate, then dried loaded on silica gel, and purified by flash chromatography using an eluent of DCM/EA (0% to 40% EA with 0.1% tfa). The main desired fraction was collected and the solvent was removed under reduced pressure to give a yellow solid (340 mg, yield 70.5%). LCMS (APCI-): c (C) 36 H 21 F 6 NO 5 Calculated value of = 661.13; actual measurement value: 661. 1 H NMR(400MHz,d 2 -TCE)δ8.57(dd,J＝19.2,8.1Hz,2H),8.18(d,J＝2.2Hz,1H),8.05(d,J＝8.0Hz,1H),8.03-7.98(m,2H),7.87(s,1H),7.72(dd,J＝8.6,2.2Hz,1H),7.48(d,J＝8.6Hz,1H),7.33(d,J＝8.3Hz,3H),7.21-7.12(m,2H),2.72(t,J＝7.6Hz,2H),2.39(t,J＝7.3Hz,2H),2.04-1.97(m,2H)。
example 6 (Ex-6)
Ex-6: 1H, 3H-thioxantho [2,1,9-def]A mixture of isochromene-1, 3-dione (458 mg,1.5 mmol), 4- (4-aminophenyl) butyric acid (537 mg,3 mmol) and DMAP (14 mg,0.11 mmol) in 10mL of DMF was heated in a microwave reactor at 165℃for 2.5 hours. The resulting solution was dropped into 60mL of acetone while stirring. An orange precipitate formed, which was filtered and washed with diethyl ether, dried in air to give an orange solid (546 mg) which was dried in vacuo at 100 ℃ Further drying in the box for 3 hours gave the desired product as an orange solid (500 mg, 71.7% yield). Confirmation by LCMS (APCI-): c (C) 28 H 19 NO 4 Calculated value of S = 465.10; actual measurement value: 465. 1 H NMR(400MHz,DMSO-d 6 )δ8.55(d,J＝8.4Hz,1H),8.52-8.46(m,2H),8.32(d,J＝8.0Hz,1H),7.78(d,J＝8.0Hz,1H),7.65-7.58(m,1H),7.52(tt,J＝7.2,5.5Hz,2H),7.37-7.30(m,2H),7.30-7.23(m,2H),2.69(t,J＝7.4Hz,2H),2.29(t,J＝7.3Hz,2H),1.88(p,J＝7.5Hz,2H)。
the following examples are synthetic procedures for many embodiments of pyrrole intermediates as described herein:
example 7 (Ex-7.3):
Ex-7.2-Compound EX-7.2, (E) -6,7,8, 9-tetrahydro-5H-benzo [7]General procedure for the synthesis of rota-ene-5-ketoxime: the compound Ex-7.1 (10.0 g,62.0 mmol), NH 2 OH HCl (6.50 g,93.0 mmol) and NaOAc (12.7 g,155.0 mmol) in EtOH/H 2 The mixture in O (45 mL/150 mL) was placed in a 500mL two-necked round bottom flask with reflux condenser. The solution was heated to 115 ℃ to reflux and held at that temperature for 1 hour. TLC (50% etoac in hexanes) showed the reaction was complete. After cooling to 0 ℃ and filtration, compound EX-7.2 was obtained as off-white solid, which was used in the next step without further purification, quantifying yield. MS (APCI): c (C) 11 H 14 NO([M+H]Calculated +) = 176, found: 176. 1 H NMR(400MHz,CDCl 3 )δ7.98(bs,1H),7.39(dd,J＝7.6Hz,1.6Hz,1H),7.30(td,J＝7.6Hz,1.6Hz,1H),7.23(td,J＝7.6Hz,1.6Hz,1H),7.13(d,J＝7.6Hz,1H),2.74(m,4H),1.78(ddd,J＝13.2Hz,6.0Hz,6.0Hz,2H),1.65(ddd,J＝12.4Hz,6.0Hz,6.0Hz,2H)。
Ex-7.3-Compound EX-7.3,1,4,5,6-tetrahydrobenzo [6,7 ]]Cyclohepta [1,2-b ]]General procedure for pyrrole synthesis: a solution of compound EX-7.2 (8.8 g,50.0 mmol) and KOH (10.1 g,180.0 mmol) in DMSO (50 mL) was placed in 250mL of a two-necked round bottom with reflux condenser A flask. The solution was degassed at room temperature and heated to 140 ℃. To this solution was added dropwise, over 5.5 hours, another solution of DCE (12.4 g,125 mmol) in DMSO (50 mL) by a syringe pump. After the DCE solution addition was completed, the reaction was cooled to room temperature, followed by pouring saturated NH 4 Cl solution (500 mL). EtOAc (500 ml x 3) was used to extract the desired product from the treatment solution. The combined organic layers were taken up over anhydrous Na 2 SO 4 Drying, concentration in vacuo and purification by flash chromatography on silica gel gave compound EX-7.3 as a pale white solid, 4.6g,50% yield using DCM (0-30%) in hexane as eluent. MS (APCI): c (C) 13 H 14 N([M+H] + ) Calculated value of (c=184, found: 184. 1 H NMR(400MHz,CDCl 3 )δ8.19(bs,1H),7.34(dd,J＝8.0Hz,1.6Hz,1H),7.22(td,J＝7.6Hz,1.6Hz,1H),7.16(dd,J＝7.6Hz,1.6Hz,1H),7.09(td,J＝7.6Hz,1.6Hz,1H),6.84(t,J＝2.8Hz,1H),6.16(t,J＝2.8Hz,1H),2.90(t,J＝6.8Hz,2H),2.83(m,2H),2.02(m,2H)。
example 8 (Ex-8.2):
compound EX-8.2,4,5-dihydro-1H-benzo [ g ]]General synthesis procedure for indole: NH is added to 2 A mixture of OH HCl (4.2 g,60.0 mmol) and KOH (3.4 g,60.0 mmol) in DMSO (50 mL) was placed in a 500mL, two-necked round bottom flask with reflux condenser. The solution was stirred at room temperature for 30 minutes. Compound EX-8.1 (7.3 g,50.0 mmol) in DMSO (25 mL) is then added. The solution was heated to 70 ℃ and held at that temperature for 30 minutes. Then, another portion of KOH (8.4 g,150.0 mmol) was added to the solution, followed by heating the solution to 140 ℃. To this solution was added dropwise, over 4 hours, another solution of DCE (9.9 g,100.0 mmol) in DMSO (25 mL) by a syringe pump. After the DCE solution addition was completed, the reaction was cooled to room temperature, followed by pouring saturated NH 4 Cl solution (200 mL). EtOAc (200 ml x 3) was used to extract the desired product from the treatment solution. The combined organic layers were taken up over anhydrous Na 2 SO 4 Drying, concentration in vacuo and purification by flash chromatography on silica afforded compound Ex-8.2 as a pale white solid, 3.7g,43% yield using DCM (0-30%) in hexane as eluent. MS (APCI): c (C) 12 H 12 N([M+H] + ) Calculated value of (c) =170, measured value: 170. 1 H NMR(400MHz,CDCl 3 )δ8.28(bs,1H),7.22(ddd,J＝17.6Hz,10.4Hz,10.4Hz,2H),7.16(t,J＝7.2Hz,1H),7.08(td,J＝7.2,1.6Hz,1H),6.76(m,1H),6.15(m,1H),2.96(t,J＝7.2Hz,2H),2.78(t,J＝7.2Hz,2H)。
example 9-synthesis of photoluminescent complex (PLC):
the following example is a synthetic procedure for many embodiments of RL-naphthalimide-BODIPY as described herein:
synthesis of PLC-1:
general procedure for Compound PLC-1.3: a 100mL 2-neck round bottom flask was fitted with an air condenser and a stirrer bar. The compound 1,4,5, 6-tetrahydrobenzo [6,7 ] was added to the flask]Cyclohepta [1,2-b ]]Pyrrole PLC-1.1 (813.1 mg,4.4 mmol) and 4-hydroxy-2, 6-dichlorobenzaldehyde PLC-1.2 (424.3 mg,2.2 mmol) were added followed by anhydrous dichloroethane (55 mL). The reaction mixture was bubbled with Ar for 30 min, then TFA (4 drops) was added. The reaction solution was stirred at room temperature overnight. After cooling the reaction to 0deg.C in an ice-water bath, tetrachloro-p-benzoquinone (731.8 mg,2.98 mmol) was added. The reaction was kept at 0℃for 30 minutes. BF was then added at 0deg.C 3 ·OET 2 (3.0 mL,24.1 mmol) and Et 3 N (1.9 mL,13.3 mmol). The reaction mixture was heated to 50 ℃ for 3 hours. The reaction mixture was loaded with silica gel and purified by flash chromatography using DCM (0-80-90%) in hexane as eluent to give pure BODIPY PLC-1.3 as a brown gold solid, 476.0mg,36% yield. MS (APCI): c (C) 33 H 24 BCl 2 F 2 N 2 O([M-H] - ) Calculated value of (d) =584, measured value: 584. 1 H NMR(400MHz,CDCl 3 )8.09(dd,J＝4.0Hz,2.0Hz,2H),7.32(dddd,J＝13.2Hz,7.2Hz,7.2Hz,2.0Hz,4H),7.22(dd,J＝6.4Hz,2.0Hz,2H),6.99(s,2H),6.43(s,2H),5.77(bs,1H),2.63(dd,J＝6.8Hz,6.8Hz,4H),2.32(bs,4H),2.03(ddd,J＝14.0Hz,6.8Hz,6.8Hz,4H)。
general procedure for Compound PLC-1: a10 mL vial was fitted with a stir bar. To the vial was added compound PLC-1.3 (25.0 mg,0.043 mmol), PLC-1.4 (24.0 mg,0.053 mmol), EDC. HCl (40.9 mg,0.21 mmol) and DMAP. TsOH (25.6 mg,0.085 mmol), followed by the addition of anhydrous DCM (1.5 mL). The reaction mixture was heated to 40 ℃ overnight. After cooling the reaction to room temperature, the reaction mixture was loaded with silica gel and purified by flash chromatography using DCM (0-5%) in EtOAc as eluent to give pure RL-naphthalimide-BODIPY PLC-1 as a dark purple solid. The solid was further triturated with MeOH (10 ml) to give RL-naphthalimide-BODIPY PLC-1, 21.0mg,48% yield. MS (APCI): c (C) 61 H 41 Cl 2 F 2 N 3 O 5 ([M-H] - ) Calculated value of (d) =1015, found: 1015. 1 H NMR(400MHz,CDCl 3 )8.66(dd,J＝18.4Hz,7.6Hz,2H),8.10(m,3H),7.99(d,J＝8.0Hz,1H),7.56(ddd,J＝8.0Hz,8.0Hz,1.6Hz,1H),7.36(m,13H),7.22(dd,J＝6.8Hz,2.0Hz,2H),6.45(s,2H)2.88(t,J＝7.6Hz,2H),2.72(t,J＝7.2Hz,2H),2.63(m,4H),2.20(m,6H),2.04(ddd,J＝6.8Hz,6.8Hz,6.8Hz,4H)。
synthesis of PLC-2:
General procedure for Compound PLC-2: a mixture of compound PLC-2.1 (31 mg,0.053 mmol), compound PLC-2.2 (43 mg,0.082 mmol), EDC. HCl (100 mg,0.52 mmol) and DMAP/p-TsOH (16 mg,0.054 mmol) in DCM (8 mL) was stirred at room temperature overnight. The resulting mixture was then loaded onto silica gel and purified by flash chromatography using an eluent of DCM/ethyl acetate (0% → 5% ethyl acetate). The main red fraction was collected and concentrated to-1 mL under reduced pressure, then 10mL methanol was added. Filtration houseThe precipitate was obtained and dried in air to give a dark red solid (41 mg, yield 70.8%). LCMS (APCI-): c (C) 67 H 46 BCl 2 F 2 N 3 O 5 Calculated value of (M-) = 1091.29; actual measurement value: 1091. 1 H NMR(400MHz,d2-TCE)δ8.56(dd,J＝19.3,8.1Hz,2H),8.21(d,J＝2.2Hz,1H),8.02(d,J＝8.1Hz,1H),7.97(t,J＝4.7Hz,2H),7.73(dd,J＝8.6,2.1Hz,1H),7.63(dd,J＝7.2,1.7Hz,2H),7.50-7.41(m,3H),7.38(dd,J＝8.0,2.2Hz,3H),7.34-7.25(m,7H),7.25-7.18(m,4H),6.40(s,2H),2.82(t,J＝7.5Hz,2H),2.67(t,J＝7.4Hz,2H),2.60-2.49(m,4H),2.24(s,4H),2.18-2.07(m,2H),2.03-1.90(m,4H)。
synthesis of PLC-3:
general procedure for Compound PLC-3: a mixture of compound PLC-3.1 (28 mg,0.048 mmol), compound PLC-2.1 (70 mg,0.08 mmol), DIC (0.1 mL,0.63 mmol), DMAP/TsOH salt (29 mg,0.1 mmol) in dry dichloromethane (5 mL) was stirred at room temperature for 40 hours. The resulting mixture was loaded on silica gel and purified by flash chromatography using an eluent of hexane/dichloromethane (50% → 100% dichloromethane). The desired fractions were collected. After removal of the solvent and washing with methanol, a dark red solid was obtained after filtration and dried in air (45 mg, 65% yield). LCMS (APCI-): c (C) 77 H 46 BCl 2 F 14 N 3 O 5 Calculated value of (M-) = 1439.27; actual measurement value: 1439. 1 H NMR(400MHz,d2-TCE)δ8.66(s,1H),8.41(s,1H),8.18(d,J＝1.5Hz,2H),7.96(d,J＝18.4Hz,6H),7.39(dd,J＝8.3,2.4Hz,3H),7.34-7.12(m,11H),6.98-6.85(m,2H),6.39(s,2H),2.82(t,J＝7.6Hz,2H),2.66(t,J＝7.4Hz,2H),2.54(d,J＝6.1Hz,4H),2.24(m,4H),2.15-2.06(m,2H),1.96(m,4H)。
synthesis of PLC-4:
general procedure for Compound PLC-4.3: a 100mL 2-neck round bottom flask was fitted with an air condenser and a stirrer bar. The flask was charged with the compound 4, 5-dihydro-1H-benzo [ g ]]Indole PLC-4.1 (203.1 mg,1.2 mmol) and 4-hydroxy-2, 6-dimethylbenzaldehyde PLC-4.2 (90.0 mg,0.6 mmol) were added followed by anhydrous dichloroethane (15 mL). The reaction mixture was bubbled with Ar for 30 min, then TFA (3 drops) was added. The reaction solution was heated to 40 ℃ and stirred overnight at 40 ℃. After cooling the reaction to 0deg.C in an ice-water bath, tetrachloro-p-benzoquinone (200.0 mg,0.8 mmol) was added. The reaction was kept at 0℃for 30 minutes. BF was then added at 0deg.C 3 ·OEt 2 (0.8 mL,6.5 mmol) and Et 3 N (0.5 mL,3.6 mmol). The reaction mixture was heated to 50 ℃ for 2 hours. The reaction mixture was loaded with silica gel and purified by flash chromatography using DCM (0-80-90%) in hexane as eluent to give pure BODIPY PLC-4.3 as a dark purple golden solid, 242.2mg,78% yield. MS (APCI): c (C) 33 H 28 BF 2 N 2 O([M+H] + ) Calculated value of (c=517, found: 517. 1 H NMR(400MHz,CDCl 3 )8.80(d,J＝8.0Hz,2H),7.44(td,J＝7.2Hz,1.6Hz,2H),7.31(td,J＝7.6Hz,1.2Hz,2H),7.25(m,2H),6.63(s,2H),6.33(s,2H),4.82(s,1H),2.91(t,J＝6.4Hz,4H),2.65(t,J＝6.4Hz,4H),2.18(s,6H)。
general procedure for Compound PLC-4: a 10mL vial was fitted with a stir bar. To the vial was added compound PLC-4.3 (25.0 mg,0.048 mmol), PLC-4.4 (27.2 mg,0.061 mmol), EDC. HCl (46.4 mg,0.24 mmol) and DMAP. TsOH (29.0 mg,0.097 mmol), followed by the addition of anhydrous DCM (1.5 mL). The reaction mixture was heated to 40 ℃ overnight. After cooling the reaction to room temperature, the reaction mixture was loaded with silica gel and purified by flash chromatography using DCM (0-5%) in EtOAc as eluent to give pure RL-naphthalimide-BODIPY PLC-4 as a blue-green solid. The solid was further triturated with MeOH (10 mL) to give RL-naphthalimide-BODIPY PLC-4, 20.1mg,44% yield. MS (APCI): c (C) 61 H 43 BF 2 N 3 O 5 ([M-H] - ) Calculated value of (1) =947, realMeasuring: 947. 1 H NMR(400MHz,CDCl 3 )8.80(d,J＝8.4Hz,2H),8.66(dd,J＝18.4Hz,8.0Hz,2H),8.11(dd,J＝8.0Hz,1.6Hz,1H),7.99(d,J＝8.0Hz,1H),7.56(ddd,J＝8.0Hz,8.0Hz,1.6Hz,1H),7.37(m,11H),7.25(m,2H),6.93(s,2H),6.35(s,2H),2.90(m,6H),2.68(m,6H),2.24(s,6H),2.20(m,2H)。
synthesis of PLC-5:
general procedure for Compound PLC-5.3: a 100mL 2-neck round bottom flask was fitted with an air condenser and a stirrer bar. The flask was charged with the compound 4, 5-dihydro-1H-benzo [ g ]]Indole PLC-5.1 (203.1 mg,1.2 mmol) and 4-hydroxy-2, 6-dichlorobenzaldehyde PLC-5.2 (114.6 mg,0.6 mmol) were then added anhydrous dichloroethane (15 mL). The reaction mixture was bubbled with Ar for 30 min, then TFA (3 drops) was added. The reaction solution was stirred at room temperature overnight. After cooling the reaction to 0deg.C in an ice-water bath, tetrachloro-p-benzoquinone (200.0 mg,0.8 mmol) was added. The reaction was kept at 0℃for 30 minutes. BF was then added at 0deg.C 3 ·OEt 2 (0.8 mL,6.5 mmol) and Et 3 N (0.5 mL,3.6 mmol). The reaction mixture was heated to 50 ℃ for 2 hours. The reaction mixture was loaded with silica gel and purified by flash chromatography using DCM (0-80-90%) in hexane as eluent to give pure BODIPY PLC-5.3 as a dark purple golden solid, 200.3mg,57% yield. MS (APCI): c (C) 31 H 20 BCl 2 F 2 N 2 O([M-H] - ) Calculated value of (d) =556, measured value: 556. 1 H NMR(400MHz,CDCl 3 )8.80(d,J＝8.0Hz,2H),7.44(td,J＝7.6Hz,1.6Hz,2H),7.32(td,J＝7.6Hz,1.2Hz,2H),7.25(m,2H),6.99(s,2H),6.35(s,2H),5.68(bs,1H),2.93(t,J＝7.6Hz,4H),2.68(t,J＝7.6Hz,4H)。
general procedure for Compound PLC-5: a 10mL vial was fitted with a stir bar. To a vial was added the compounds PLC-5.3 (25.0 mg,0.045 mmol), PLC-5.4 (25.2 mg,0.056 mmol), EDC. HCl (43.0 mg,0.22 mmol) and DMAP. TsOH (26.9 mg,0.089 mmol), followed by the addition of anhydrous DCM (1.5 mL). The reaction mixture was heated to 40 ℃ overnight. After cooling the reaction to room temperature, the reaction mixture was loaded with silica gel and purified by flash chromatography using DCM (0-5%) in EtOAc as eluent to give pure RL-naphthalimide-BODIPY PLC-5 as a green solid. The solid was further triturated with MeOH (10 mL) to give RL-naphthalimide-BODIPY PLC-5, 16.0mg,36% yield. MS (APCI): c (C) 59 H 37 BCl 2 F 2 N 3 O 5 ([M-H] - ) Calculated value of (c=986, found: 986. 1 H NMR(400MHz,CDCl 3 )8.80(d,J＝8.4Hz,2H),8.66(dd,J＝18.0Hz,8.0Hz,2H),8.11(dd,J＝8.0Hz,1.6Hz,1H),7.99(d,J＝8.0Hz,1H),7.56(ddd,J＝8.0Hz,8.0Hz,1.6Hz,1H),7.34(m,15H),6.37(s,2H),2.90(m,6H),2.70(dd,J＝14.8Hz,7.6Hz,6H),2.24(ddd,J＝7.6Hz,7.6Hz,7.6Hz,2H)。
synthesis of PLC-6:
general procedure for Compound PLC-6.3: a 100mL 2-neck round bottom flask was fitted with an air condenser and a stirrer bar. The compound 1,4,5, 6-tetrahydrobenzo [6,7 ] was added to the flask]Cyclohepta [1,2-b ]]Pyrrole PLC-6.1 (220.0 mg,1.2 mmol) and 4-hydroxy-2, 6-dimethoxybenzaldehyde PLC-6.2 (109.3 mg,0.6 mmol) were added followed by anhydrous dichloroethane (15 ml). The reaction mixture was bubbled with Ar for 30 min, then TFA (3 drops) was added. The reaction solution was heated to 40 ℃ and stirred overnight at 40 ℃. After cooling the reaction to 0deg.C in an ice-water bath, tetrachloro-p-benzoquinone (200.0 mg,0.8 mmol) was added. The reaction was kept at 0℃for 30 minutes. BF was then added at 0deg.C 3 ·OEt 2 (0.8 mL,6.5 mmol) and Et 3 N (0.5 mL,3.6 mmol). The reaction mixture was heated to 50 ℃ for 2 hours. The reaction mixture was loaded with silica gel and purified by flash chromatography using DCM (0-80-90%) in hexane as eluent to give pure BODIPY PLC-6.3 as a dark purple solid, 28.0mg,8% yield. MS (APCI): c (C) 35 H 30 BF 2 N 2 O 3 ([M-H]Calculated = 576, found: 576. 1 H NMR(400MHz,CDCl3)8.10(d,J＝7.6Hz,2H),7.29(dddd,J＝17.2Hz,7.2Hz,7.2Hz,4H),7.21(dd,J＝7.2Hz,2H),6.48(s,2H),6.19(s,2H),3.72(s,6H),2.62(dd,J＝6.8Hz,6.8Hz,4H),2.29(bs,4H),2.02(ddd,J＝14.0Hz,7.2Hz,7.2Hz,4H)。
general procedure for Compound PLC-6: a 10mL vial was fitted with a stir bar. To the vial was added compound PLC-6.3 (28.0 mg,0.049 mmol), PLC-6.4 (27.3 mg,0.061 mmol), EDC. HCl (46.6 mg,0.24 mmol) and DMAP. TsOH (29.2 mg,0.097 mmol), followed by the addition of anhydrous DCM (1.5 mL). The reaction mixture was heated to 40 ℃ overnight. After cooling the reaction to room temperature, the reaction mixture was loaded with silica gel and purified by flash chromatography using DCM (0-5%) in EtOAc as eluent to give pure RL-naphthalimide-BODIPY PLC-6 as dark red-purple solid. The solid was further triturated with MeOH (10 mL) to give RL-naphthalimide-BODIPY PLC-6,4.0mg,8% yield. MS (APCI): c (C) 63 H 47 BF 2 N 3 O 7 ([M-H] - ) Calculated value of (c) 1007, found: 1007. 1 H NMR(400MHz,CDCl 3 )8.66(dd,J＝18.4Hz,8.0Hz,2H),8.11(dd,J＝8.0Hz,1.6Hz,3H),7.99(d,J＝8.0Hz,1H),7.56(ddd,J＝8.0Hz,8.0Hz,1.6Hz,1H),7.41(m,4H),7.32(m,7H),7.21(dd,J＝7.2Hz,1.6Hz,2H),6.50(s,2H),6.49(s,2H),3.77(s,6H),2.89(t,J＝7.2Hz,2H),2.72(t,J＝7.2Hz,2H),2.62(m,4H),2.30(bs,2H),2.21(ddd,J＝7.6Hz,7.6Hz,7.6Hz,4H),2.02(ddd,J＝6.8Hz,6.8Hz,6.8Hz,4H)。
synthesis of PLC-7:
General procedure for Compound PLC-7.3: a 100mL 2-neck round bottom flask was fitted with an air condenser and a stirrer bar. The flask was charged with the compound 4, 5-dihydro-1H-benzo [ g ]]Indole PLC-7.1 (203.1 mg,1.2 mmol) and 4-hydroxy-2, 6-dimethoxybenzaldehyde PLC-7.2 (109.3 mg,0.6 mmol) were added followed by anhydrous dichloroethane (15 mL). The reaction mixture is reactedBubbling with Ar for 30 min, then TFA (3 drops) was added. The reaction solution was heated to 40 ℃ and stirred overnight at 40 ℃. After cooling the reaction to 0deg.C in an ice-water bath, tetrachloro-p-benzoquinone (200.0 mg,0.8 mmol) was added. The reaction was kept at 0℃for 30 minutes. BF was then added at 0deg.C 3 ·OEt 2 (0.8 mL,6.5 mmol) and Et 3 N (0.5 mL,3.6 mmol). The reaction mixture was heated to 50 ℃ for 2 hours. The reaction mixture was loaded with silica gel and purified by flash chromatography using DCM (0-80-90%) in hexane as eluent to give pure BODIPY PLC-7.3 as a brown gold solid, 78.4mg,24% yield. MS (APCI): c (C) 33 H 28 BF 2 N 2 O 3 ([M+H] + ) Calculated value of (i) =549, measured value: 549. 1 H NMR(400MHz,CDCl 3 )8.80(d,J＝8.0Hz,2H),7.43(t,J＝8.0Hz,2H),7.29(m,2H),7.23(d,J＝7.2Hz,2H),6.41(s,2H),6.17(s,2H),5.05(bs,1H),3.69(s,6H),2.90(t,J＝6.8Hz,4H),2.65(t,J＝6.8Hz,4H)。
general procedure for Compound PLC-7: a 10mL vial was fitted with a stir bar. To the vial was added compound PLC-7.3 (25.0 mg,0.045 mmol), PLC-7.4 (25.6 mg,0.057 mmol), EDC. HCl (43.7 mg,0.23 mmol) and DMAP. TsOH (27.4 mg,0.091 mmol), followed by the addition of anhydrous DCM (1.5 mL). The reaction mixture was heated to 40 ℃ overnight. After cooling the reaction to room temperature, the reaction mixture was loaded with silica gel and purified by flash chromatography using DCM (0-5%) in EtOAc as eluent to give pure RL-naphthalimide-BODIPY PLC-7 as a dark green solid. The solid was further triturated with MeOH (10 mL) to give RL-naphthalimide-BODIPY PLC-7, 23.0mg,51% yield. MS (APCI): c (C) 61 H 43 BF 2 N 3 O 7 ([M-H] - ) Calculated = 979, found: 979. 1 H NMR(400MHz,CDCl 3 )8.81(d,J＝8.0Hz,2H),8.67(dd,J＝18.4Hz,7.6Hz,2H),8.11(dd,J＝8.0Hz,1.6Hz,1H),8.00(d,J＝8.0Hz,1H),7.56(ddd,J＝8.0Hz,8.0Hz,1.6Hz,1H),7.34(m,11H),7.23(m,2H),6.46(s,2H),6.43(s,2H),3.73(s,6H),2.89(dd,J＝14.0Hz,6.4Hz,6H),2.68(m,6H),2.24(ddd,J＝7.6Hz,7.6Hz,7.6Hz,2H)。
synthesis of PLC-8:
general procedure for Compound PLC-8.3: a 100mL 2-neck round bottom flask was fitted with an air condenser and a stirrer bar. The compound 1,4,5, 6-tetrahydrobenzo [6,7 ] was added to the flask]Cyclohepta [1,2-b ]]Pyrrole PLC-8.1 (220.0 mg,1.2 mmol) and 4-hydroxy-2, 6-dimethylbenzaldehyde PLC-8.2 (90.0 mg,0.6 mmol) were added followed by anhydrous dichloroethane (15 ml). The reaction mixture was bubbled with Ar for 30 min, then TFA (3 drops) was added. The reaction solution was heated to 40 ℃ overnight. After cooling the reaction to 0deg.C in an ice-water bath, tetrachloro-p-benzoquinone (200.0 mg,0.8 mmol) was added. The reaction was kept at 0℃for 20 minutes. BF was then added at 0deg.C 3 ·OEt 2 (0.8 mL,6.5 mmol) and Et 3 N (0.5 mL,3.6 mmol). The reaction mixture was heated to 50 ℃ for 2 hours. The reaction mixture was loaded with silica gel and purified by flash chromatography using DCM (0-80-90%) in hexane as eluent to give pure BODIPY PLC-8.3 as a dark purple solid, 162.5mg,48% yield. MS (APCI): c (C) 35 H 30 BF 2 N 2 O([M-H] - ) Calculated value=543, measured value: 543. 1 H NMR(400MHz,CDCl 3 )8.08(d,J＝7.2Hz,2H),8.02(bs,1H),7.28(m,6H),6.66(bs,2H),6.41(bs,2H),2.96(bs,4H),2.89(bs,4H),2.62(m,4H),2.22(s,6H)。
general procedure for PLC-8: a 10mL vial was fitted with a stir bar. To the vial was added compound PLC-8.3 (25.0 mg,0.046 mmol), PLC-8.4 (25.8 mg,0.057 mmol), EDC. HCl (44.1 mg,0.23 mmol) and DMAP. TsOH (27.6 mg,0.092 mmol), followed by the addition of anhydrous DCM (1.5 mL). The reaction mixture was heated to 40 ℃ overnight. After cooling the reaction to room temperature, the reaction mixture was loaded with silica gel and purified by flash chromatography using DCM (0-5%) in EtOAc as eluent to give pure RL-naphthalimide-BODIPY PLC-8 as a dark purple solid. The solid was further triturated with MeOH (10 mL) to give RL-naphthalimide-BODIPY PLC-8 31.0mg,69% yield. MS (APCI): c (C) 63 H 47 BF 2 N 3 O 5 ([M-H] - ) Calculated = 975, found: 975. 1 H NMR(400MHz,CDCl 3 )8.66(dd,J＝18.4Hz,7.6Hz,2H),8.10(td,J＝8.0Hz,1.6Hz,2H),8.08(bs,1H),7.99(d,J＝8.0Hz,1H),7.56(ddd,J＝8.0Hz,8.0Hz,1.6Hz,1H),7.36(m,11H),7.22(dd,J＝7.2Hz,2.0Hz,2H),6.95(s,2H),6.43(s,2H)2.88(t,J＝7.2Hz,2H),2.70(t,J＝7.2Hz,2H),2.62(m,4H),2.29(s,6H),2.20(m,6H),2.02(ddd,J＝6.8Hz,6.8Hz,6.8Hz,4H)。
synthesis of PLC-9:
general procedure for PLC-9: a 10mL vial was fitted with a stir bar. To the vial was added compound PLC-9.1 (25.0 mg,0.048 mmol), PLC-9.2 (27.2 mg,0.061 mmol), EDC. HCl (46.4 mg,0.24 mmol) and DMAP. TsOH (29.0 mg,0.097 mmol), followed by the addition of anhydrous DCM (1.5 mL). The reaction mixture was heated to 40 ℃ overnight. After cooling the reaction to room temperature, the reaction mixture was loaded with silica gel and purified by flash chromatography using DCM (0-5%) in EtOAc as eluent to give pure RL-naphthalimide-BODIPY PLC-9 as a dark green solid. The solid was further triturated with MeOH (10 mL) to give RL-naphthalimide-BODIPY PLC-9, 25.0mg,54% yield. MS (APCI): c (C) 61 H 43 BF 2 N 3 O 5 ([M-H] - ) Calculated = 947, found: 947. 1 H NMR(400MHz,CDCl 3 )8.67(dd,J＝18.4Hz,7.6Hz,2H),8.10(m,3H),7.99(d,J＝8.0Hz,1H),7.56(ddd,J＝8.0Hz,8.0Hz,1.6Hz,1H),7.34(m,11H),7.23(m,2H),6.95(m,2H),2.88(t,J＝7.2Hz,2H),2.70(t,J＝7.2Hz,2H),2.62(m,4H),2.29(s,6H),2.20(ddd,J＝7.6Hz,7.6Hz,7.6Hz,6H),2.24(ddd,J＝7.6Hz,7.6Hz,7.6Hz,2H)。
synthesis of PLC-10:
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general procedure for PLC-10: a 10mL vial was fitted with a stir bar. To the vial were added compound PLC-10.1 (30.0 mg,0.055 mmol), PLC-10.2 (32.1 mg,0.069 mmol), EDC. HCl (52.7 mg,0.275 mmol) and DMAP. TsOH (33.0 mg,0.110 mmol), followed by the addition of anhydrous DCM (1.5 mL). The reaction mixture was heated to 40 ℃ overnight. After cooling the reaction to room temperature, the reaction mixture was loaded with silica gel and purified by flash chromatography using DCM (0-5%) in EtOAc as eluent to give pure RL-naphthalimide-BODIPY PLC-10 as a dark purple solid. The solid was further triturated with MeOH (10 mL) to give RL-naphthalimide-BODIPY PLC-10, 51.0mg,94% yield. MS (APCI): c (C) 63 H 48 BF 2 N 3 O 4 S([M-H] - ) Calculated value of (c=991, measured value: 991. 1 H NMR(400MHz,CDCl 3 )8.68(d,J＝8.0Hz,1H),8.48(d,J＝8.0Hz,1H),8.26(m,2H),8.09(m,2H),7.56(d,J＝8.0Hz,1H),7.44(m,5H),7.32(m,6H),7.22(m,2H),6.95(s,2H),6.43(s,2H),2.88(t,J＝7.6Hz,2H),2.70(t,J＝7.6Hz,2H),2.62(m,4H),2.29(s,6H),2.20(m,6H),2.24(ddd,J＝6.8Hz,6.8Hz,6.8Hz,4H)。
synthesis of PLC-11:
general procedure for PLC-11: a 10mL vial was fitted with a stir bar. To the vial was added compound PLC-11.1 (30.0 mg,0.058 mmol), PLC-11.2 (33.8 mg,0.073 mmol), EDC. HCl (55.6 mg,0.290 mmol) and DMAP. TsOH (34.8 mg,0.116 mmol), followed by the addition of anhydrous DCM (1.5 mL). The reaction mixture was heated to 40 ℃ overnight. After cooling the reaction to room temperature, the reaction mixture was loaded with silica gel and purified by flash chromatography using DCM (0-5%) in EtOAc as eluent to give pure RL-naphthalimide-BODIPY PLC-11 as a dark green solid. The solid was further triturated with MeOH (10 mL) to give RL-naphthalimide-BODIPY PLC-11, 40.0mg,72% yield. MS (APCI): c (C) 61 H 44 BF 2 N 3 O 4 S([M-H] - ) Calculated = 963, found: 963. 1 H NMR(400MHz,CDCl 3 )8.81(d,J＝8.0Hz,2H),8.68(d,J＝8.0Hz,1H),8.48(d,J＝8.0Hz,1H),8.26(m,2H),7.56(d,J＝8.0Hz,1H),7.44(m,7H),7.29(m,6H),6.93(s,2H),6.35(s,2H),2.90(m,6H),2.68(m,6H),2.24(s,6H),2.19(m,2H)。
synthesis of PLC-12:
general procedure for PLC-12: a 10mL vial was fitted with a stir bar. To the vial was added compound PLC-12.1 (30.0 mg,0.051 mmol), PLC-12.2 (29.8 mg,0.064 mmol), EDC. HCl (48.9 mg,0.255 mmol) and DMAP. TsOH (30.6 mg,0.102 mmol), followed by the addition of anhydrous DCM (1.5 mL). The reaction mixture was heated to 40 ℃ overnight. After cooling the reaction to room temperature, the reaction mixture was loaded with silica gel and purified by flash chromatography using DCM (0-5%) in EtOAc as eluent to give pure RL-naphthalimide-BODIPY PLC-12 as a dark green solid. The solid was further triturated with MeOH (10 mL) to give RL-naphthalimide-BODIPY PLC-12, 31.0mg,61% yield. MS (APCI): c (C) 59 H 38 BCl 2 F 2 N 3 O 4 S([M+H] + ) Calculated value of (c) =1005, found: 1005. 1 H NMR(400MHz,CDCl 3 )8.81(m,2H),8.68(d,J＝8.0Hz,1H),8.48(d,J＝8.0Hz,1H),8.26(m,2H),7.56(d,J＝8.0Hz,1H),7.43(m,7H),7.31(m,6H),7.25(m,2H),6.37(s,2H),2.93(m,4H),2.87(d,J＝7.6Hz,2H),2.69(m,6H),2.24(s,6H),2.19(ddd,J＝7.6Hz,7.6Hz,7.6Hz,2H)。
synthesis of PLC-13:
general procedure for PLC-13: a 10mL vial was fitted with a stir bar. Into the vial were added the compounds PLC-13.1 (30.0 mg,0.058 mmol), PLC-13.2 #33.8mg,0.073 mmol), EDC. HCl (55.6 mg,0.290 mmol) and DMAP. TsOH (34.8 mg,0.116 mmol) followed by the addition of anhydrous DCM (1.5 mL). The reaction mixture was heated to 40 ℃ overnight. After cooling the reaction to room temperature, the reaction mixture was loaded with silica gel and purified by flash chromatography using DCM (0-5%) in EtOAc as eluent to give pure RL-naphthalimide-BODIPY PLC-13 as a dark green solid. The solid was further triturated with MeOH (10 mL) to give RL-naphthalimide-BODIPY PLC-13, 29.0mg,52% yield. MS (APCI): c (C) 61 H 44 BF 2 N 3 O 4 S([M-H] - ) Calculated = 963, found: 963. 1 H NMR(400MHz,CDCl 3 )8.81(m,2H),8.68(d,J＝8.0Hz,1H),8.48(d,J＝8.0Hz,1H),8.26(m,2H),7.56(d,J＝8.0Hz,1H),7.43(m,9H),7.29(m,6H),7.24(m,2H),2.88(m,6H),2.72(t,J＝7.2Hz,2H),2.54(m,4H),2.21(ddd,J＝7.2Hz,7.2Hz,7.2Hz,2H)。
synthesis of PLC-14:
general procedure for PLC-14: a 10mL vial was fitted with a stir bar. To the vial was added compound PLC-14.1 (30.0 mg,0.055 mmol), PLC-14.2 (31.8 mg,0.068 mmol), EDC. HCl (52.7 mg,0.275 mmol) and DMAP. TsOH (33.0 mg,0.110 mmol), followed by the addition of anhydrous DCM (1.5 mL). The reaction mixture was heated to 40 ℃ overnight. After cooling the reaction to room temperature, the reaction mixture was loaded with silica gel and purified by flash chromatography using DCM (0-5%) in EtOAc as eluent to give pure RL-naphthalimide-BODIPY PLC-14 as a dark green solid. The solid was further triturated with MeOH (10 mL) to give RL-naphthalimide-BODIPY PLC-14, 44.0mg,80% yield. MS (APCI): c (C) 61 H 44 BF 2 N 3 O 6 S([M-H] - ) Calculated value of (c=995, found: 995. 1 H NMR(400MHz,CDCl 3 )8.81(m,2H),8.68(d,J＝8.0Hz,1H),8.48(d,J＝8.0Hz,1H),8.26(m,2H),7.56(d,J＝8.0Hz,1H),7.44(m,7H),7.29(m,4H),7.23(m,2H),6.46(s,2H),6.42(s,2H),3.73(s,6H),2.89(m,6H),2.68(m,6H),2.21(ddd,J＝7.6Hz,7.6Hz,7.6Hz,2H)。
synthesis of PLC-15:
general procedure for PLC-15: a 10mL vial was fitted with a stir bar. To the vial were added compound PLC-15.1 (22.0 mg,0.037 mmol), PLC-15.2 (20.7 mg,0.046 mmol), EDC. HCl (35.5 mg,0.185 mmol) and DMAP. TsOH (22.2 mg,0.074 mmol), followed by anhydrous DCM (1.5 ml) and THF (1.5 ml). The reaction mixture was heated to 60 ℃ overnight. After cooling the reaction to room temperature, the reaction mixture was loaded with silica gel and purified by flash chromatography using DCM (0-5%) in EtOAc as eluent to give pure RL-naphthalimide-BODIPY PLC-15 as a dark green solid. The solid was further triturated with MeOH (10 mL) to give RL-naphthalimide-BODIPY PLC-15,6.0mg,16% yield. MS (APCI): c (C) 67 H 52 BF 2 N 3 O 5 ([M-H] - ) Calculated = 1027, found: 1027. 1 H NMR(400MHz,CDCl 3 )8.68(d,J＝8.0Hz,1H),8.64(d,J＝8.0Hz,1H),8.30(m,2H),8.11(dd,J＝8.0Hz,J＝1.6Hz,1H),7.99(d,J＝8.0Hz,1H),7.56(td,J＝8.0Hz,J＝1.6Hz,1H),7.41(m,10H),7.31(m,3H),7.00(s,2H),6.19(s,2H),2.89(t,J＝7.6Hz,2H),2.71(t,J＝7.6Hz,2H),2.51(s,6H),2.21(m,2H),1.98(m,16H)。
synthesis of PLC-16:
general procedure for PLC-16.3: a 100mL 2-neck round bottom flask was fitted with an air condenser and a stirrer bar. The compound 1,4,5, 6-tetrahydrobenzo [6,7 ] was added to the flask]Cyclohepta [1,2-b ]]Pyrrole PLC-16.1 (542.0 mg,2.96 mmol) and 4-hydroxy-2, 6-difluorobenzaldehyde PLC-16.2 (222.6 mg,1.4 mmol) were added followed by anhydrous dichloromethane (20 ml). The reaction mixture is used Ar was bubbled for 30 minutes, then p-TsOH.H was added 2 O (17.0 mg,0.14 mmol). The reaction solution was stirred at room temperature for 2 hours. DDQ (381.4 mg,1.68 mmol) was added after complete consumption of aldehyde starting material. The reaction was kept at room temperature for 1 hour. Then add ET 3 N (1.2 mL,8.40 mmol) and the reaction was kept at room temperature for 30 min, followed by the addition of BF at room temperature 3 ·OEt 2 (2.1 mL,12.6 mmol). The reaction mixture was kept at room temperature for another 1 hour. The reaction mixture was loaded with silica gel and purified by flash chromatography using DCM (0-80-90%) in hexane as eluent to give pure BODIPY PLC-16.3 as a blue gold solid, 279.0mg,36% yield. MS (APCI): c (C) 33 H 25 BF 4 N 2 O([M-H] - ) Calculated value of (2) =552, found: 552.
general procedure for PLC-16: a 10mL vial was fitted with a stir bar. To the vial was added compound PLC-16.3 (30.0 mg,0.054 mmol), PLC-16.4 (30.5 mg,0.068 mmol), EDC. HCl (51.8 mg,0.270 mmol) and DMAP. TsOH (32.4 mg,0.108 mmol), followed by the addition of anhydrous DCM (1.5 ml). The reaction mixture was heated to 40 ℃ overnight. After cooling the reaction to room temperature, the reaction mixture was loaded with silica gel and purified by flash chromatography using DCM (0-5%) in EtOAc as eluent to give pure RL-naphthalimide-BODIPY PLC-16 as a green purple solid. The solid was further triturated with MeOH (10 mL) to give RL-naphthalimide-BODIPY PLC-16, 25.0mg,47% yield. MS (APCI): c (C) 61 H 42 BF 4 N 3 O 5 ([M-H] - ) Calculated value of (c=983, found: 983. 1 H NMR(400MHz,CDCl 2 CDCl 2 )8.65(d,J＝8.0Hz,1H),8.61(d,J＝8.0Hz,1H),8.13(dd,J＝8.0Hz,J＝1.6Hz,1H),8.02(m,3H),7.60(td,J＝8.0Hz,J＝1.6Hz,1H),7.39(m,13H),7.04(m,2H),6.63(s,2H),2.91(t,J＝7.2Hz,2H),2.77(t,J＝7.2Hz,2H),2.64(m,4H),2.70(dd,J＝6.8Hz,J＝6.8Hz,6H),2.20(m,9H)。
synthesis of PLC-17:
general procedure of PLC-17.3: a 100mL 2-neck round bottom flask was fitted with an air condenser and a stirrer bar. The flask was charged with the compound 4, 5-dihydro-1H-benzo [ g ]]Indole PLC-17.1 (507.7 mg,3.0 mmol) and 4-hydroxy-2, 6-difluorobenzaldehyde PLC-17.2 (225.9 mg,1.43 mmol) were added followed by anhydrous dichloromethane (20 ml). The reaction mixture was bubbled with Ar for 30 min, then p-TsOH H was added 2 O (17.4 mg,0.143 mmol). The reaction solution was stirred at room temperature for 2 hours. DDQ (392.4 mg,1.74 mmol) was added after complete consumption of aldehyde starting material. The reaction was kept at room temperature for 1 hour. Then add ET 3 N (1.2 mL,8.64 mmol) and the reaction was kept at room temperature for 30 min, followed by the addition of BF at room temperature 3 ·OEt 2 (1.6 mL,12.96 mmol). The reaction mixture was kept at room temperature for another 1 hour. The reaction mixture was loaded with silica gel and purified by flash chromatography using DCM (0-80-90%) in hexane as eluent to give pure BODIPY PLC-17.3 as a brown gold solid, 211.0mg,28% yield. MS (APCI): c (C) 31 H 21 BF 4 N 2 O([M-H] - ) Calculated value of (d) =524, measured value: 524. 1 H NMR(400MHz,CDCl 3 )8.80(d,J＝8.0Hz,2H),7.44(m,2H),7.32(m,2H),7.23(m,2H),6.57(m,2H),6.49(s,2H),2.92(m,4H),2.69(m,4H)。
general procedure for PLC-17: a 10mL vial was fitted with a stir bar. To the vial was added compound PLC-17.3 (30.0 mg,0.057 mmol), PLC-17.4 (32.1 mg,0.072 mmol), EDC. HCl (54.6 mg, 0.284 mmol) and DMAP. TsOH (34.2 mg,0.114 mmol), followed by the addition of anhydrous DCM (1.5 ml). The reaction mixture was heated to 40 ℃ overnight. After cooling the reaction to room temperature, the reaction mixture was loaded with silica gel and purified by flash chromatography using DCM (0-5%) in EtOAc as eluent to give pure RL-naphthalimide-BODIPY PLC-17 as a dark green solid. The solid was further triturated with MeOH (10 ml) to give RL-naphthalimide-BODIPY PLC-17, 38.0mg,70% yield. MS (APCI): c (C) 59 H 38 BF 4 N 3 O 5 ([M-H] - ) Calculation of (2)Value = 955, found: 955. 1 H NMR(400MHz,CDCl 3 )8.80(m,2H),8.68(d,J＝8.0Hz,1H),8.64(d,J＝8.0Hz,1H),8.11(dd,J＝8.0Hz,J＝1.6Hz,1H),7.99(d,J＝8.0Hz,1H),7.56(td,J＝8.0Hz,J＝1.6Hz,1H),7.38(m,12H),7.24(m,1H),6.94(m,2H),6.50(s,2H),2.90(m,6H),2.70(dd,J＝6.8Hz,J＝6.8Hz,6H),2.19(m,2H)。
synthesis of PLC-18:
general procedure for PLC-18: a 10mL vial was fitted with a stir bar. To the vial was added compound PLC-18.1 (30.0 mg,0.054 mmol), PLC-18.2 (31.6 mg,0.068 mmol), EDC. HCl (51.8 mg,0.270 mmol) and DMAP. TsOH (32.4 mg,0.108 mmol), followed by the addition of anhydrous DCM (1.5 ml). The reaction mixture was heated to 40 ℃ overnight. After cooling the reaction to room temperature, the reaction mixture was loaded with silica gel and purified by flash chromatography using DCM (0-5%) in EtOAc as eluent to give pure RL-naphthalimide-BODIPY PLC-18 as a dark purple solid. The solid was further triturated with MeOH (10 ml) to give RL-naphthalimide-BODIPY PLC-18, 43.0mg,78% yield. MS (APCI): c (C) 63 H 48 BF 2 N 3 O 6 S([M-H] - ) Calculated value of (c) =1023, measured value: 1023. 1 H NMR(400MHz,CDCl 3 )8.68(d,J＝8.0Hz,1H),8.47(d,J＝8.0Hz,1H),8.26(m,2H),8.11(m,2H),7.56(d,J＝8.0Hz,1H),7.44(m,5H),7.31(m,6H),7.21(m,2H),6.50(s,2H),6.49(s,2H),3.77(s,6H),2.89(t,J＝7.2Hz,2H),2.71(t,J＝7.2Hz,2H),2.62(m,4H),2.28(m,6H),2.02(ddd,J＝7.2Hz,J＝7.2Hz,J＝7.2Hz,4H)。
synthesis of PLC-19:
general procedure for PLC-19: a 10mL vial was fitted with a stir bar. Into the vial was added the compounds PLC-19.1 (30.0 mg,0.057 mmol), PLC-19.2 (33.3 mg,0.072 mmol), EDC. HCl (54.6 mg, 0.284 mmol) and DMAP. TsOH (34.2 mg,0.114 mmol) followed by the addition of anhydrous DCM (1.5 ml). The reaction mixture was heated to 40 ℃ overnight. After cooling the reaction to room temperature, the reaction mixture was loaded with silica gel and purified by flash chromatography using DCM (0-5%) in EtOAc as eluent to give pure RL-naphthalimide-BODIPY PLC-19 as a dark blue-green solid. The solid was further triturated with MeOH (10 ml) to give RL-naphthalimide-BODIPY PLC-19, 43.0mg,78% yield. MS (APCI): c (C) 59 H 38 BF 4 N 3 O 4 S([M-H]Calculated = 971, found: 971. 1 H NMR(400MHz,CDCl 3 )8.80(m,2H),8.67(d,J＝8.0Hz,1H),8.47(d,J＝8.0Hz,1H),8.25(m,2H),7.56(d,J＝8.0Hz,1H),7.44(m,7H),7.31(m,5H),7.24(m,1H),6.94(m,2H),6.50(s,2H),2.91(m,6H),2.70(m,6H),2.20(ddd,J＝7.6Hz,J＝7.6Hz,J＝7.6Hz,4H)。
synthesis of PLC-20:
general procedure for PLC-20: a 10mL vial was fitted with a stir bar. To the vial were added compound PLC-20.1 (30.0 mg,0.054 mmol), PLC-20.2 (31.6 mg,0.068 mmol), EDC. HCl (51.8 mg,0.270 mmol) and DMAP. TsOH (32.4 mg,0.108 mmol), followed by the addition of anhydrous DCM (1.5 ml). The reaction mixture was heated to 40 ℃ overnight. After cooling the reaction to room temperature, the reaction mixture was loaded with silica gel and purified by flash chromatography using DCM (0-5%) in EtOAc as eluent to give pure RL-naphthalimide-BODIPY PLC-20 as a dark blue-green solid. The solid was further triturated with MeOH (10 ml) to give RL-naphthalimide-BODIPY PLC-20, 30.0mg,56% yield. MS (APCI): c (C) 61 H 42 BF 4 N 3 O 4 S([M-H]Calculated = 999, found: 999. 1 H NMR(400MHz,CDCl 2 CDCl 2 )8.65(d,J＝8.0Hz,1H),8.44(d,J＝8.0Hz,1H),8.28(m,2H),8.03(m,2H),7.61(d,J＝8.0Hz,1H),7.47(m,5H),7.33(m,8H),7.04(m,2H),6.63(s,2H),2.91(t,J＝7.2Hz,2H),2.76(t,J＝7.2Hz,2H),2.64(m,4H),2.35(bs,3H),2.13(m,6H)。
synthesis of PLC-21:
general procedure for PLC-21: a 10mL vial was fitted with a stir bar. To the vial were added compound PLC-21.1 (30.0 mg,0.055 mmol), PLC-21.2 (31.0 mg,0.069 mmol), EDC. HCl (52.7 mg,0.275 mmol) and DMAP. TsOH (33.0 mg,0.110 mmol), followed by the addition of anhydrous DCM (1.5 ml). The reaction mixture was heated to 40 ℃ overnight. After cooling the reaction to room temperature, the reaction mixture was loaded with silica gel and purified by flash chromatography using DCM (0-5%) in EtOAc as eluent to give pure RL-naphthalimide-BODIPY PLC-21 as a dark blue-green solid. The solid was further triturated with MeOH (10 ml) to give RL-naphthalimide-BODIPY PLC-21, 39.0mg,72% yield. MS (APCI): c (C) 63 H 48 BF 2 N 3 O 5 ([M-H]Calculated = 975, found: 975.1H NMR (400 MHz, CDCl) 2 CDCl 2 )8.76(m,2H),8.66(d,J＝8.0Hz,1H),8.61(d,J＝8.0Hz,1H),8.13(dd,J＝8.0Hz,J＝1.6Hz,1H),8.02(d,J＝8.0Hz,1H),7.60(td,J＝8.0Hz,J＝1.6Hz,1H),7.38(m,13H),7.01(s,2H),2.91(m,6H),2.72(t,J＝7.2Hz,2H),2.57(m,4H),2.25(s,6H),2.23(m,2H),1.42(s,6H)。
Synthesis of PLC-22:
general procedure for PLC-22: a 10mL vial was fitted with a stir bar. To the vial were added compound PLC-22.1 (30.0 mg,0.055 mmol), PLC-22.2 (29.0 mg,0.069 mmol), EDC. HCl (52.7 mg,0.275 mmol) and DMAP. TsOH (33.0 mg,0.110 mmol), followed by the addition of anhydrous DCM (1.5 ml). The reaction mixture was heated to 40 ℃ overnight. After cooling the reaction to room temperature, the reaction mixture was charged withSilica gel supported and purified by flash chromatography using DCM (0-5%) in EtOAc as eluent gave pure RL-naphthalimide-BODIPY PLC-22 as a dark blue-green solid. The solid was further triturated with MeOH (10 ml) to give RL-naphthalimide-BODIPY PLC-22, 33.0mg,63% yield. MS (APCI): c (C) 61 H 44 BF 2 N 3 O 5 ([M-H] - ) Calculated = 947, found: 947. 1 H NMR(400MHz,CDCl 2 CDCl 2 )8.67(d,J＝8.0Hz,1H),8.62(d,J＝8.0Hz,1H),8.14(dd,J＝8.0Hz,J＝1.6Hz,1H),8.05(m,2H),8.02(d,J＝8.0Hz,1H),7.66(m,2H),7.60(td,J＝8.0Hz,J＝1.6Hz,1H),7.37(m,11H),7.01(s,2H),6.46(s,2H),4.04(s,2H),2.63(m,4H),2.30(m,9H),2.04(m,4H)。
synthesis of PLC-23:
general procedure for PLC-23: a 10mL vial was fitted with a stir bar. To the vial was added compound PLC-23.1 (30.0 mg,0.051 mmol), PLC-23.2 (27.0 mg,0.064 mmol), EDC. HCl (48.9 mg,0.255 mmol) and DMAP. TsOH (30.6 mg,0.102 mmol), followed by the addition of anhydrous DCM (1.5 ml). The reaction mixture was heated to 40 ℃ overnight. After cooling the reaction to room temperature, the reaction mixture was loaded with silica gel and purified by flash chromatography using DCM (0-5%) in EtOAc as eluent to give pure RL-naphthalimide-BODIPY PLC-23 as a dark blue-green solid. The solid was further triturated with MeOH (10 ml) to give RL-naphthalimide-BODIPY PLC-23, 17.0mg,34% yield. MS (APCI): c (C) 59 H 38 BCl 2 F 2 N 3 O 5 ([M-H] - ) Calculated value of (c=988, found: 988. 1 H NMR(400MHz,CDCl 2 CDCl 2 )8.67(d,J＝8.0Hz,1H),8.62(d,J＝8.0Hz,1H),8.14(dd,J＝8.0Hz,J＝1.6Hz,1H),8.05(m,2H),8.03(d,J＝8.0Hz,1H),7.65(m,2H),7.60(td,J＝8.0Hz,J＝1.6Hz,1H),7.43(s,2H),7.38(m,11H),6.48(s,2H),4.06(s,2H),2.64(m,4H),2.33(bs,3H),2.05(m,4H)。
synthesis of PLC-24:
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general procedure for PLC-24: a mixture of compound PLC-24.1 (16 mg,0.027 mmol), compound PLC-24.2 (19 mg,0.04 mmol), EDC. HCl (52 mg,0.27 mmol) and DMAP/p-TsOH (8 mg,0.027 mmol) in DCM (5 mL) was stirred at room temperature overnight. The resulting mixture was then loaded onto silica gel and purified by flash chromatography using an eluent of hexane/DCM (50% → 100% DCM), then DCM/ethyl acetate (0% → 5% ethyl acetate). The main red fraction was collected and concentrated under reduced pressure. The resulting solid was triturated with methanol, filtered and dried in air to give a dark red solid (18 mg, 64.6% yield). LCMS (APCI-): c (C) 61 H 42 BCl 2 F 2 N 3 O 4 Calculated value of S (M-) = 1031.23; actual measurement value: 1031. 1 H NMR(400MHz,d2-TCE)δ8.56(d,J＝8.2Hz,1H),8.35(d,J＝8.0Hz,1H),8.19(dd,J＝8.8,4.5Hz,2H),7.97(s,2H),7.51(d,J＝8.0Hz,1H),7.38(dt,J＝7.3,2.4Hz,5H),7.29(d,J＝9.3Hz,6H),7.24-7.15(m,4H),6.40(s,2H),2.82(t,J＝7.5Hz,2H),2.67(t,J＝7.4Hz,2H),2.54(d,J＝6.8Hz,4H),2.24(s,4H),2.11(td,J＝13.4,11.8,5.9Hz,2H),2.04-1.89(m,4H)。
synthesis of PLC-25:
general procedure for PLC-25: a mixture of compound PLC-2.1 (20 mg,0.034 mmol), compound EX-5 (27 mg,0.051 mmol), EDC. HCl (60 mg,0.31 mmol) and DMAP/p-TsOH (8.8 mg,0.03 mmol) in DCM (4 mL) was stirred at room temperature overnight. The resulting mixture was then loaded onto silica gel and purified by flash chromatography using an eluent of DCM/ethyl acetate (0% → 10% ethyl acetate). The main red fraction was collected and concentrated to 0.5mL under reduced pressure, then 10mL methanol was added. Filtering the obtained precipitate The precipitate was dried in air to give a dark red solid (23 mg, 62% yield). LCMS (APCI-): c (C) 69 H 44 BCl 2 F 8 N 3 O 5 Calculated value of (M-) = 1227.26; actual measurement value: 1227. 1 H NMR(400MHz,d2-TCE)δ8.58(dd,J＝19.5,8.1Hz,2H),8.18(d,J＝2.2Hz,1H),8.06(d,J＝8.1Hz,1H),8.02(d,J＝1.5Hz,2H),7.97(t,J＝4.6Hz,2H),7.87(s,1H),7.72(dd,J＝8.6,2.1Hz,1H),7.49(d,J＝8.6Hz,1H),7.39(d,J＝8.2Hz,2H),7.34(d,J＝8.3Hz,1H),7.32-7.25(m,6H),7.25-7.18(m,4H),6.40(s,2H),2.82(t,J＝7.5Hz,2H),2.67(t,J＝7.4Hz,2H),2.61-2.50(m,4H),2.24(s,4H),2.13(q,J＝7.4Hz,2H),2.04-1.90(m,4H)。
synthesis of PLC-26:
compound PLC-26.1 (6- (4- (tert-butyl) -2-nitrophenoxy) -1H, 3H-benzo [ de ]]Isochromene-1, 3-dione): A1L 2N round bottom flask was charged with a stir bar and placed in an aluminum heating block. The flask was fitted with a fin condenser, gas connector and flow controller. The flask was purged with argon. 6-bromo-1H, 3H-benzo [ de ] added to the flask]Isochromene-1, 3-dione (40.0 mmol,11.084 g) and 4- (tert-butyl) -2-nitrophenol (60.0 mmol, 11.710 g), naOH (20.0 mmol,800 mg), copper powder (20.0 mmol, 1.271g) and anhydrous NMP (150 mL). The flask was closed and stirred under argon. The heating block was set to 170 ℃, and the reaction mixture was heated at that temperature overnight. LCMS showed the reaction was complete. The reaction mixture was cooled to room temperature. To the flask was added 1N HCl (44 mL) and water (175 mL). After stirring for about 15 minutes, the resulting precipitate was filtered off and washed with water. The dried precipitate was dissolved in warm ethyl acetate and filtered warm to remove small amounts of insoluble material. Ethyl acetate was removed under vacuum. The resulting solid was triturated with hot methanol and then allowed to cool to room temperature. The precipitate obtained is filtered off and washed with methanol. The solid was dried in a vacuum oven at 100 ℃. 8.18g (52% yield) was obtained. MS (APCI): c (C) 22 H 17 NO 6 (M+H) meterCalculated value = 392; actual measurement value: 392.1H NMR (400 MHz, tetrachloroethane-d) 2 )δ8.82(dd,J＝8.5,1.2Hz,1H),8.71(dd,J＝7.3,1.2Hz,1H),8.49(d,J＝8.3Hz,1H),8.16(d,J＝2.4Hz,1H),7.91(dd,J＝8.4,7.3Hz,1H),7.80(dd,J＝8.6,2.4Hz,1H),7.34(d,J＝8.6Hz,1H),6.91(d,J＝8.3Hz,1H),1.43(s,9H)。
Compound PLC-26.2 (6- (2-amino-4- (tert-butyl) phenoxy) -1H, 3H-benzo [ de ]]Isochromene-1, 3-dione): a 250mL 2N round bottom flask was charged with a stir bar and fitted with a fin condenser, gas connector and flow controller. The flask was placed in an aluminum heating block. The flask was purged with argon. Into the flask were added compound PLC-26.1 (10.0 mmol, 3.910 g) and SnCl 2 .2H 2 O (40.0 mmol,9.024 g) followed by 2-methyl THF (70 mL) and concentrated hydrochloric acid (4.0M) (100 mmol,25 mL). The flask was closed and heated to 90 ℃ under argon for 30 minutes, at which time TLC showed complete conversion to product. The reaction mixture was cooled to room temperature and then the pH was adjusted to pH 8 with 2N NaOH. The resulting precipitate was filtered off. The solid was extracted with 2-methyl THF (8×100 mL). The layers were separated and the organic layer was dried over MgSO 4 Dried, filtered and evaporated to dryness. The resulting solid was dried at 120 ℃. The product was obtained in quantitative yield. MS (APCI): c (C) 22 H 19 NO 4 Calculated value of (m+h) =362; actual measurement value: 362.1H NMR (400 MHz, tetrachloroethane-d) 2 )δ8.88(dd,J＝8.4,1.2Hz,1H),8.69(dd,J＝7.3,1.2Hz,1H),8.48(d,J＝8.4Hz,1H),7.89(dd,J＝8.4,7.3Hz,1H),7.03-6.93(m,3H),6.88(dd,J＝8.4,2.3Hz,1H),1.35(s,9H)。
Compound PLC-26.3 (9- (tert-butyl) -1H, 3H-isochromeno [6,5, 4-mna)]Xanthene-1, 3-dione): naNO was filled into 40mL vials 2 (30.0 mmol,2.070 g), water (10 mL), and a stir bar. The vials were placed in an ice water bath and stirred to dissolve. A100 mL round bottom flask was charged with stirring bar and compound PLC-26.2 (4.00 mmol, 1.4476 g), hydrochloric acid (37%) (20.0 mmol,12.1M,1.65 mL) and glacial acetic acid (30 mL). The flask was placed in an ice-water bath and stirred for about 1 minute, then the addition of sodium nitrite solution was started in small portions within 3 minutes. The solution was stirred in an ice-water bath for 1 hour. A1L 2N round bottom flask was passed through an eccentric neck (off-center neg)) The funnel is clamped at an angle such that the dropping funnel inserted into the neck will fall into the top of the stirring vortex. The other neck was fitted with a finned condenser. To the flask was added a large stirring bar, cuSO 4 .5H 2 O (27.4 mmol,6.842 g) and water (80 mL). Near the end of the one hour waiting time for the diazonium salt, the copper (II) solution was placed in an aluminum heating block and the temperature was set to 130 ℃. When the copper (II) solution reached 130 ℃, the diazonium solution was transferred to the dropping funnel. The reaction was stirred at maximum RPM and the diazonium solution was added dropwise over about 20 minutes. The resulting solution was stirred at 130 ℃ for 2 minutes, then removed from the heated block and stirred overnight at room temperature. The precipitate is filtered off and washed with water. The crude precipitate was dried, then dissolved and evaporated in vacuo on silica gel. Purification by column chromatography on silica gel (220 g, equilibrated 50% hexane/DCM, elution 50% (2 CV) 100% DCM (20 CV), isocratic DCM (15 CV)>0％EtOAc/DCM(0CV)/>1% EtOAc/DCM (10 CV)). Product tailing (tails). All fractions with product were collected and evaporated to dryness in vacuo. 528mg (38% yield) was obtained. MS (APCI): c (C) 22 H 16 O 4 Calculated value of (m+h) =345; actual measurement value: 345.1H NMR (400 MHz, tetrachloroethane-d) 2 )δ8.61(d,J＝7.9Hz,1H),8.56(d,J＝8.4Hz,1H),8.05(d,J＝2.2Hz,1H),8.01(d,J＝8.0Hz,1H),7.66(dd,J＝8.8,2.2Hz,1H),7.38(d,J＝8.7Hz,1H),7.34(d,J＝8.4Hz,1H),1.44(s,9H)。
Compound PLC-26.4 (4- (4- (9- (tert-butyl) -1, 3-dioxo-1H-xantheno [2,1, 9-def)]Isoquinolin-2 (3H) -yl) phenyl) butanoic acid): a stirring rod was fitted with 100mL of 2N RBF and equipped with a fin-type condenser, gas connector and flow control valve. The flask was flushed with argon and charged with compound PLC-26.3 (1.525 mmol,525 mg), 4- (4-aminobenzene)Butyric acid (3.05 mmol, 540 mg) and DMAP (0.1113 mmol,14 mg). To the flask was added anhydrous DMF (10 mL). The flask was sealed and stirred under argon. The heating block was set to 175 ℃, and the reaction was heated and stirred for 6.5 hours, then stirred overnight at room temperature. Acetone (25 mL) and water (25 mL) were added to the reaction mixture. The precipitate was stirred for 5 minutes and then filtered off and washed with 1:1 water: acetone. The precipitate was dried under a stream of argon at 120 ℃. 738mg (96% yield) was obtained. MS (APCI): c (C) 32 H 27 NO 5 Calculated value of (m+h) =506; actual measurement value: 506.1H NMR (400 MHz, DMSO-d 6) delta 12.12 (s, 1H), 8.48-8.29 (m, 3H), 8.23 (d, J=2.3 Hz, 1H), 7.68 (dd, J=8.8, 2.3Hz, 1H), 7.43-7.30 (m, 4H), 7.25 (d, J=7.9 Hz, 2H), 2.75-2.64 (m, 2H), 2.30 (t, J=7.4 Hz, 2H), 1.88 (p, J=7.5 Hz, 2H), 1.41 (s, 9H).
Compound PLC-26 (3, 5-dichloro-4- (19, 19-difluoro-6,7,11,12,13,19-hexahydro-5H-18 l4,19l 4-benzo [3',4 ]']Cyclohepta [1',2':4,5]Pyrrolo [1,2-c]Benzo [3',4 ]']Cyclohepta [1',2':4,5]Pyrrolo [2,1-f][1,3,2]Diazaborane-9-yl) phenyl 4- (4- (9- (tert-butyl) -1, 3-dioxo-1H-xantheno [2,1, 9-def)]Isoquinolin-2 (3H) -yl) phenyl) butyrate): a40 mL vial was filled with stirring bar, 3, 5-dichloro-4- (19, 19-difluoro-6,7,11,12,13,19-hexahydro-5H-18 l4,19l 4-benzo [3',4 ]']Cyclohepta [1',2':4,5]Pyrrolo [1,2-c]Benzo [3',4 ]']Cyclohepta [1',2':4,5]Pyrrolo [2,1-f][1,3,2]Diazaborane-9-yl) phenol (0.050 mmol,29.3 mg), compound PLC-26.4 (0.075 mmol,37.9 mg), DMAP. PTsOH salt (0.100 mmol,29.4 mg) and EDC.HCl (0.075 mmol,14.4 mg) were then charged into anhydrous DCM (10 mL). The vials were capped and stirred at room temperature for 4.5 hours. The reaction mixture was diluted with hexane (to-35 mL) and loaded into a solids loading cartridge (-20 g SiO) 2 ) And (3) upper part. The reaction mixture was purified by column chromatography on silica gel (120 g, equilibrated 100% toluene, eluted 100% (5 CV)5% EtOAc/toluene (30 CV)). The product-containing fractions were evaporated to dryness and re-purified by flash chromatography on silica gel (solid loading, 120g column, equilibrated 40% dcm/hexane, 40% (2 CV) eluted +. >100％DCM(10CV)/>Isocratic DCM until complete elution of compound). The product-containing fractions were evaporated to dryness in vacuo. 19.8mg (37% yield) was obtained. MS (APCI): c (C) 65 H 50 BCl 2 F 2 N 3 O 5 Calculated value of (M-) =1071; actual measurement value: 1071.1H NMR (400 MHz, dichloromethane-d) 2 )δ8.65(d,J＝7.9Hz,1H),8.58(d,J＝8.3Hz,1H),8.12(d,J＝2.3Hz,1H),8.05(d,J＝8.0Hz,1H),8.00(d,J＝6.8Hz,2H),7.63(dd,J＝8.7,2.3Hz,1H),7.47-7.43(m,2H),7.40(s,2H),7.38-7.24(m,10H),6.51(s,2H),2.90(t,J＝7.6Hz,2H),2.75(t,J＝7.4Hz,2H),2.64(t,J＝6.8Hz,4H),2.43-2.26(m,4H),2.21(p,J＝7.5Hz,2H),2.05(p,J＝7.0Hz,4H),1.44(s,9H)。
Synthesis of PLC-27:
compound PLC-27.2 (2- (4- (9- (tert-butyl) -1, 3-dioxo-1H-xantheno [2,1, 9-def)]Isoquinolin-2 (3H) -yl) phenyl) acetic acid): compound PLC-27.2 was synthesized from compound PLC-27.1 (1.191 mmol,410 mg), 2- (4-aminophenyl) acetic acid (2.98 mmol,450 mg) and DMAP (0.0869 mmol,11 mg) in a similar manner to compound PLC-26.4. The product was obtained in quantitative yield. MS (APCI): c (C) 30 H 23 NO 5 Calculated value of (m+h) =478; actual measurement value: 478.1H NMR (400 MHz, DMSO-d 6) delta 8.48 (d, J=7.9 Hz, 1H), 8.44 (d, J=8.3 Hz, 1H), 8.38 (d, J=8.1 Hz, 1H), 8.27 (d, J=2.4 Hz, 1H), 7.69 (dd, J=8.8, 2.3Hz, 1H), 7.45-7.38 (m, 4H), 7.31-7.27 (m, 2H), 3.68 (s, 2H), 1.41 (s, 9H).
Compound PLC-27 (3, 5-dichloro-4- (19, 19-difluoro-6,7,11,12,13,19-hexahydro-5H-18 l4,19l 4-benzo [3',4 ]']Cyclohepta [1',2':4,5]Pyrrolo [1,2-c]Benzo [3',4 ]']Cyclohepta [1',2':4,5]Pyrrolo [2,1-f][1,3,2]Diazaborane-9-yl) phenyl 2- (4- (9- (tert-butyl) -13-dioxo-1H-xantheno [2,1,9-def ]Isoquinolin-2 (3H) -yl) phenyl) acetate): compound PLC-27 was prepared from 3, 5-dichloro-4- (19, 19-difluoro-6,7,11,12,13,19-hexahydro-5H-18 l4,19l 4-benzo [3',4 ]']Cyclohepta [1',2':4,5]Pyrrolo [1,2-c]Benzo [3',4 ]']Cyclohepta [1',2':4,5]Pyrrolo [2,1-f][1,3,2]Diazaborane-9-yl) phenol (0.100 mmol,58.6 mg), compound PLC-27.2 (0.150 mmol,71.6 mg), DMAP. PTsOH salt (0.200 mmol,58.8 mg) and EDC/HCl (0.150 mmol,28.8 mg) were synthesized followed by anhydrous DCM (10 mL). The vials were capped and stirred overnight at room temperature. The next morning, more of the compound edc.hcl (0.200 mmol,38.8 mg) was added and stirred at room temperature for 90 minutes. More edc.hcl (0.200 mmol,38.3 mg) was added and stirring was continued for 2 hours at room temperature. Compound PLC-27.2 (0.075 mmol,35.8 mg) was added and stirring was continued for 2 hours at room temperature. The crude reaction mixture was purified by flash chromatography on silica gel (solid loading, 120g column, equilibrated 40% dcm/hexane, 40% eluted (2 CV)100％DCM(10CV)/>Isocratic DCM until complete elution of compound)). The product-containing fractions were evaporated to dryness in vacuo. 11.0mg (11% yield) was obtained. MS (APCI): c (C) 63 H 46 BCl 2 F 2 N 3 O 5 Calculated value of (M-) =1043; actual measurement value: 1043. 1 h NMR (400 MHz, dichloromethane-d) 2 )δ8.67(d,J＝7.9Hz,1H),8.60(d,J＝8.4Hz,1H),8.13(d,J＝2.3Hz,1H),8.07(d,J＝8.0Hz,1H),8.00(d,J＝6.9Hz,2H),7.64(dd,J＝8.8,2.3Hz,1H),7.62-7.58(m,2H),7.44(s,2H),7.40-7.27(m,10H),6.51(s,2H),4.07(s,2H),2.70-2.58(m,4H),2.33(s,4H),2.05(p,J＝7.1Hz,4H),1.44(s,9H)。
Synthesis of Compound PLC-28
Compound PLC-28.2- (4-(9-bromo-1, 3-dioxo-1H-xantheno [2,1, 9-def)]Isoquinolin-2 (3H) -yl) phenyl) acetic acid: a mixture of PLC-28.1 (400.0 mg,1.1 mmol), 4-aminophenylacetic acid (329.4 mg,2.2 mmol) and DMAP (9.3 mg,0.080 mmol) in DMF (8 mL) was degassed at room temperature. The mixture was then heated to 165 ℃ and held at that temperature for 3 hours. Shows a conversion of 95% with no observable side reactions. The mixture was cooled to 50 ℃. It was then poured into an acetone solution (40 mL) that had been pre-cooled by a water-ice bath. The mixture was kept at 0 ℃ for 2 hours, then the solids were collected by vacuum filtration and washed with acetone (4 mL) at room temperature with stirring overnight. And dried in a vacuum oven at 100 ℃ for 3 hours to provide pure compound PLC-28.2 as a yellowish brown solid in 395.0mg,73% yield. MS (APCI): c (C) 26 H 14 BrNO 5 ([M+H] + ) Calculated value of (c) =500, found: 500.1H NMR (400 MHz, CDCl) 2 CDCl 2 )δ8.65(d,J＝8.0Hz,1H),8.62(d,J＝8.0Hz,1H),8.21(dd,J＝6.4Hz,2.4Hz,1H),7.99(bs,1H),7.95(t,J＝7.6Hz,1H),7.67(dd,J＝8.4Hz,2.4Hz,1H),7.53(d,J＝8.0Hz,2H),7.37(d,J＝8.4Hz,1H),7.32(m,3H),2.94(s,2H)。
Compound PLC-28.3-2- (4- (9- (4-isopropylphenyl) -1, 3-dioxo-1H-xantheno [2,1, 9-def)]Isoquinolin-2 (3H) -yl) phenyl) acetic acid: PLC-28.2 (175.0 mg,0.35 mmol), 4-isopropylphenyl boronic acid (114.8 mg,0.70 mmol), pd (dppf) Cl 2 (18.0 mg,0.025 mmol) and K 2 CO 3 (130.4 mg,0.95 mmol) in THF-DMF-H 2 The mixture in O (10 mL/2mL/1 mL) was degassed at room temperature. The mixture was then heated to 80 ℃ and held at that temperature overnight. TLC and LCMS showed the reaction was complete. The mixture was cooled to room temperature. To this was then added 0.1HCl (75 mL) and EtOAc (75 mL). Once isolated by a separatory funnel, the aqueous solution was further extracted with THF (75 ml x 3) after saturation with NaCl. The combined organic phases were taken up in anhydrous Na 2 SO 4 Dried, then filtered and concentrated under a rotary evaporator, and purified by flash chromatography on silica gel using 0-40% etoac and 0.1% tfa in DCM as eluent to give PLC-28.3 as a yellow solid, 70.0mg,yield 37%. MS (APCI): c (C) 35 H 25 NO 5 ([M-H] - ) Calculated value of (c=539), measured value: 539. 1 H NMR(400MHz,CDCl 2 CDCl 2 )δ8.66(d,J＝7.6Hz,1H),8.61(d,J＝8.4Hz,1H),8.26(s,1H),8.06(d,J＝8.0Hz,1H),7.79(dd,J＝8.4Hz,2.0Hz,1H),7.45(m,11H),3.81(s,2H),3.01(quintet,J＝7.2Hz,1H),1.33(d,J＝7.2Hz,6H)。
synthesis of Compound PLC-28: the 25mL vial was fitted with a stir bar. To the vial were added compound PLC-28.4 (44.0 mg,0.075 mmol), PLC-28.3 (81.0 mg,0.15 mmol), EDC. HCl (71.9 mg,0.38 mmol) and DMAP. TsOH (45.0 mg,0.15 mmol), followed by anhydrous DCM (4.4 ml). The reaction mixture was heated to 40 ℃ overnight. After cooling the reaction to room temperature, the reaction mixture was loaded with silica gel and purified by flash chromatography using DCM (0-4%) in EtOAc as eluent to give pure RL-naphthalimide-BODIPY PLC-28 as a dark blue solid. The solid was further triturated with MeOH (15 ml) to give RL-naphthalimide-BODIPY PLC-28, 46.0mg,55% yield. MS (APCI): c (C) 68 H 48 BCl 2 F 2 N 3 O 5 ([M-H] - ) Calculated value of (c) =1106, measured value: 1106. 1 H NMR(400MHz,CDCl 2 CDCl 2 )8.67(d,J＝8.0Hz,1H),8.63(d,J＝8.0Hz,1H),8.29(d,J＝2.4Hz,1H),8.11(d,J＝8.0Hz,1H),8.05(m,2H),7.81(dd,J＝8.0Hz,J＝2.4Hz,1H),7.65(m,4H),7.51(d,J＝8.0Hz,1H),7.39(m,11H),7.30(m,2H),6.49(s,2H),4.07(s,2H),3.01(pentet,J＝6.8Hz,1H),2.64(m,4H),2.33(bs,3H),2.06(m,4H),1.33(d,J＝6.8Hz,6H)。
synthesis of Compound PLC-29
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Compound 29.1-2- (4- (1, 3-dioxo-9- (4- (trifluoromethyl) phenyl) -1H-xantheno [2,1, 9-def)]Isoquinolin-2 (3H) -yl) phenyl) acetic acid: a 100mL vial was equipped with a stir bar. Into the vial, the mixture was prepared in THF/DMF/H 2 Compound PLC-28.2 (400.0 mg, 0.8) in O (22 ml/4.4ml/2.2 ml)0 mmol), 4- (trifluoromethyl) phenylboronic acid (262.2 mg,1.6 mmol), pd (dppf) Cl 2 (41.0 mg,0.056 mmol) and K 2 CO 3 (298.0 mg,2.2 mmol) was degassed at room temperature. The reaction mixture was heated to 80 ℃ and the reaction was maintained at that temperature overnight. TLC was used to monitor the reaction. After completion, the reaction was worked up by adding 0.1N HCl (150 ml) and EtOAc (150 ml). The aqueous phase was further extracted by THF (150 ml x 3). The combined organic phases were taken up in anhydrous Na 2 SO 4 Dried, concentrated under rotary evaporator, and purified by flash chromatography using DCM (0-40% with 0.1% tfa) in EtOAc as eluent to give the pure RL-naphthalimide derivative PLC-29.1 as a yellow/yellowish brown solid. 363.0mg,80% yield. MS (APCI): c (C) 33 H 18 F 3 NO 5 ([M+H] + ) Calculated value of (c) =566, found: 566. 1 H NMR(400MHz,DMSO-d 6 )8.76(m,1H),8.56(m,2H),8.52(dd,J＝8.0Hz,J＝3.2Hz,1H),8.15(m,2H),8.06(m,1H),7.94(d,J＝8.0Hz,2H),7.66(dd,J＝8.0Hz,J＝4.0Hz,1H),7.53(m,1H),7.45(d,J＝8.0Hz,2H),7.33(d,J＝8.0Hz,2H),3.72(s,2H)。
compound PLC-29: the 25mL vial was fitted with a stir bar. To the vial was added compound PLC-28.4 (40.0 mg,0.068 mmol), PLC-29.1 (77.5 mg,0.137 mmol), EDC. HCl (65.2 mg,0.340 mmol) and DMAP. TsOH (41.1 mg,0.137 mmol), followed by the addition of anhydrous DCM (4 ml). The reaction mixture was heated to 40 ℃ overnight. After cooling the reaction to room temperature, the reaction mixture was loaded with silica gel and purified by flash chromatography using DCM (0-4%) in EtOAc as eluent to give pure RL-naphthalimide-BODIPY PLC-29 as a dark blue solid. The solid was further triturated with MeOH (15 ml) to give RL-naphthalimide-BODIPY PLC-29, 46.0mg,60% yield. MS (APCI): c (C) 66 H 41 BCl 2 F 5 N 3 O 5 ([M-H] - ) Calculated value of (c=1132, found: 1132. 1 H NMR(400MHz,CDCl 2 CDCl 2 )8.69(d,J＝8.0Hz,1H),8.65(d,J＝8.0Hz,1H),8.30(d,J＝2.0Hz,1H),8.11(d,J＝8.0Hz,1H),8.06(m,2H),7.82(m,5H),7.65(m,2H),7.55(d,J＝8.0Hz,1H),7.39(m,9H),7.30(m,2H),6.48(s,2H),4.07(s,2H),2.63(m,4H),2.33(bs,3H),2.06(m,4H)。
synthesis of Compound PLC-30
PLC-30.1-2- (4- (9- (3, 5-bis (trifluoromethyl) phenyl) -1, 3-dioxo-1H-xantheno [2,1, 9-def)]Isoquinolin-2 (3H) -yl) phenyl) acetic acid: a 100mL vial was equipped with a stir bar. Into the vial, the mixture was prepared in THF/DMF/H 2 Compound PLC-28.2 (400.0 mg,0.80 mmol), 3, 5-bis (trifluoromethyl) phenylboronic acid (262.2 mg,1.6 mmol), pd (dppf) Cl in O (22 ml/4.4ml/2.2 ml) 2 (41.0 mg,0.056 mmol) and K 2 CO 3 (412.6 mg,2.2 mmol) was degassed at room temperature. The reaction mixture was heated to 80 ℃ and the reaction was maintained at that temperature overnight. TLC was used to monitor the reaction. After completion, the reaction was worked up by adding 0.1N HCl (150 ml) and EtOAc (150 ml). The aqueous phase was further extracted by THF (150 ml x 3). The combined organic phases were taken up in anhydrous Na 2 SO 4 Dried, concentrated under rotary evaporator, and purified by flash chromatography using DCM (0-40% with 0.1% tfa) in EtOAc as eluent to give the pure RL-naphthalimide derivative PLC-30.1 as a yellow/yellowish brown solid. 311.0mg,61% yield. MS (APCI): c (C) 34 H 17 F 6 NO 5 ([M+H] + ) Calculated = 634, measured: 634. 1 H NMR(400MHz,DMSO-d 6 )8.73(m,1H),8.46(m,5H),8.10(m,2H),7.57(m,1H),7.42(d,J＝8.0Hz,2H),7.40(m,1H),7.30(d,J＝8.0Hz,2H),3.72(s,2H)。
compound PLC-30: the 25mL vial was fitted with a stir bar. To the vial were added compound PLC-28.4 (40.0 mg,0.068 mmol), PLC-30.1 (86.8 mg,0.137 mmol), EDC. HCl (65.2 mg,0.340 mmol) and DMAP. TsOH (41.1 mg,0.137 mmol), followed by the addition of anhydrous DCM (4 ml). The reaction mixture was heated to 40 ℃ overnight. After cooling the reaction to room temperature, the reaction mixture was loaded with silica gel and purified by flash chromatography using DCM (0-4%) in EtOAc as The eluent gave pure RL-naphthalimide-BODIPY PLC-30 as a dark blue solid. The solid was further triturated with MeOH (15 ml) to give RL-naphthalimide-BODIPY PLC-30, 76.0mg,93% yield. MS (APCI): c (C) 67 H 40 BCl 2 F 8 N 3 O 5 ([M-H] - ) Calculated value of (d) =1200, measured value: 1200. 1 H NMR(400MHz,CDCl 2 CDCl 2 )8.70(d,J＝8.0Hz,1H),8.66(d,J＝8.0Hz,1H),8.28(d,J＝2.0Hz,1H),8.15(d,J＝8.0Hz,1H),8.06(m,4H),7.96(m,1H),7.82(dd,J＝8.0Hz,J＝2.0Hz,1H),7.65(m,2H),7.58(d,J＝8.0Hz,1H),7.39(m,9H),7.30(m,2H),6.48(s,2H),4.07(s,2H),2.63(m,4H),2.33(bs,3H),2.05(m,4H)。
synthesis of Compound PLC-31
PLC-31.1-2- (4- (9- (4- (tert-butyl) phenyl) -1, 3-dioxo-1H-xantheno [2,1, 9-def)]Isoquinolin-2 (3H) -yl) phenyl) acetic acid: PLC-28.2 (175.0 mg,0.35 mmol), 4-tert-butylphenylboronic acid (124.6 mg,0.70 mmol), pd (dppf) Cl 2 (18.0 mg,0.025 mmol) and K 2 CO 3 (130.4 mg,0.95 mmol) in THF-DMF-H 2 The mixture in O (10 mL/2mL/1 mL) was degassed at room temperature. The mixture was then heated to 80 ℃ and held at that temperature overnight. TLC and LCMS showed the reaction was complete. The mixture was cooled to room temperature. To this was then added 0.1HCl (75 mL) and EtOAc (75 mL). Once isolated by a separatory funnel, the aqueous solution was further extracted with THF (75 ml x 3) after saturation with NaCl. The combined organic phases were taken up in anhydrous Na 2 SO 4 Dried, then filtered and concentrated under rotary evaporator, and purified by flash chromatography on silica gel using 0-40% etoac and 0.1% tfa in DCM as eluent to give PLC-31.1 as a yellow solid, 76.0mg,39% yield. MS (APCI): c (C) 36 H 27 NO 5 ([M-H] - ) Calculated value of (d) =553, found: 553. 1 H NMR(400MHz,CDCl 2 CDCl 2 )δ8.69(d,J＝8.0Hz,1H),8.64(d,J＝8.4Hz,1H),8.24(d,J＝8.4Hz,1H),8.03(d,J＝8.0Hz,1H),7.76(dd,J＝8.4Hz,2.0Hz,1H),7.53(m,7H),7.33(m,4H),3.77(s,2H),1.40(s,9H)。
compound PLC-31: the 25mL vial was fitted with a stir bar. To the vial were added compound PLC-28.4 (40.0 mg,0.068 mmol), PLC-31.1 (75.8 mg,0.137 mmol), EDC. HCl (65.2 mg,0.340 mmol) and DMAP. TsOH (41.1 mg,0.137 mmol), followed by the addition of anhydrous DCM (4 ml). The reaction mixture was heated to 40 ℃ overnight. After cooling the reaction to room temperature, the reaction mixture was loaded with silica gel and purified by flash chromatography using DCM (0-4%) in EtOAc as eluent to give pure RL-naphthalimide-BODIPY PLC-31 as a dark blue solid. The solid was further triturated with MeOH (15 ml) to give RL-naphthalimide-BODIPY PLC-31, 40.0mg,52% yield. MS (APCI): c (C) 69 H 50 BCl 2 F 2 N 3 O 5 ([M-H] - ) Calculated value of (c=1120, measured value: 1120. 1 H NMR(400MHz,CDCl 2 CDCl 2 )8.69(d,J＝8.0Hz,1H),8.63(d,J＝8.0Hz,1H),8.30(d,J＝2.0Hz,1H),8.11(d,J＝8.0Hz,1H),8.06(m,2H),7.82(dd,J＝8.0Hz,J＝2.0Hz,1H),7.65(m,4H),7.54(m,3H),7.39(m,9H),7.30(m,2H),6.49(s,2H),4.07(s,2H),2.63(m,4H),2.33(bs,3H),2.06(m,4H),1,40(s,9H)。
synthesis of Compound PLC-32
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Compound PLC-32.1
General procedure for Compound PLC-32.1: ex-4.3 (6.3 g,17.159mmol,1 eq) was suspended in 35mL anhydrous DMSO and glycine (2.31 g,30.77mmol,1.8 eq) was added to the reaction mixture at room temperature. The resulting mixture was stirred at 130 ℃ for 1 hour (mixture was insoluble) and then heated to 160 ℃ for 1 hour, LMCMS showed the reaction was complete. After cooling to room temperature, the solid product was filtered, washed with water (250 mL) and then dried in a vacuum oven to give 6.5g of a greenish yellow solid in 90% yield. 1 H NMR(400MHz,DMSO-d 6 )δ8.65(s,1H),8.50(s,1H),8.46(d,J＝8.2Hz,2H),8.09(d,J＝8.0Hz,2H),7.99(d,J＝8.7Hz,1H),7.87(d,J＝8.0Hz,2H),7.58(d,J＝8.6Hz,1H),7.45(d,J＝8.4Hz,1H),4.71(s,2H)。
Compound PLC-32.2
General procedure for Compound PLC-32.2: PLC-32.1 (4.24 g,10.0mmol,1 eq) was suspended in 2-MeTHF (150 ml), H 2 O (5.0 ml) was added 4- (t-butyl) phenylboronic acid (3.56 g,20mmol,2 eq), K 2 CO 3 (2.76g，20mmol，2eq)、Pd(dppf)Cl 2 DCM (163.3 mg,0.2mmol,0.02 eq). The reaction mixture was degassed 3 times by Vac-Fill Argon cycle, stirred and heated at 95 ℃ under Argon atmosphere for 12 hours. After cooling to room temperature, ethyl acetate (150 ml) was added and acidified to pH 4-5 with 1N HCl. The organic layer was washed with water, separated and concentrated. The residue was stirred in DMF (15 mL), filtered to give a solid, which was washed with MeOH (50 mL) and then dried in a vacuum oven to give 4.1g of a green yellow solid product in 85% yield. MS (APCI): c (C) 20 H 10 BrNO 5 Calculated value of (M-H) =423; actual measurement value: 423. 1 H NMR(400MHz,DMSO-d 6 )δ8.33(d,J＝6.1Hz,3H),8.24(d,J＝7.9Hz,1H),7.95(s,1H),7.78(d,J＝8.3Hz,1H),7.70(d,J＝7.9Hz,2H),7.50(d,J＝7.9Hz,2H),7.39(d,J＝8.3Hz,1H),7.29(d,J＝8.2Hz,1H),4.52(s,2H),2.89(s,3H),2.73(s,3H),2.54-2.47(m,21H),1.34(s,10H)。
compound PLC-32
General procedure for Compound PLC-32: PLC-32.2 (71.62 mg,0.15mmol,1.5 eq) was suspended in anhydrous DCM (10.0 ml). To the mixture was added PLC-2.1 (58.5 mg,0.1mmol,1 eq), DMAP-pTSA (58.8 mg,0.2mmol,2 eq), EDC.HCl (57.5 mg,0.3mmol,3 eq), then stirred at room temperature under argon atmosphere for 5 hours, diluted with DCM (150 ml), filtered, the solid was washed with 50ml DCM, the filtrate was collected and loaded to 80g SiO 2 On the column, elution was performed with Hex-DCM (1/1), DCM only, then 0.5% EA in DCM. The good fractions were concentrated and then washed with MeOH to give 80mg in 96% yield. MS (APCI): c (C) 63 H 46 BCl 2 F 2 N 3 O 5 (MCalculated value of (-) =1044; actual measurement value: 1044. 1 H NMR(400MHz,d 2 -TCE)δ8.63(d,J＝7.9Hz,1H),8.58(d,J＝8.3Hz,1H),8.20(d,J＝2.1Hz,1H),8.01(d,J＝8.1Hz,1H),7.98-7.91(m,2H),7.73(dd,J＝8.7,2.1Hz,1H),7.59-7.51(m,2H),7.49-7.44(m,2H),7.42(d,J＝8.6Hz,1H),7.38(s,2H),7.32(d,J＝8.3Hz,1H),7.27(dt,J＝7.3,3.7Hz,4H),7.20(dt,J＝5.1,3.7Hz,2H),6.35(s,2H),5.18(s,2H),2.54(t,J＝6.7Hz,4H),2.22(s,4H),1.99-1.90(m,4H),1.31(s,10H)。
synthesis procedure of Compound PLC-33
Compound PLC-33.1
General procedure for Compound PLC-33.1: PLC-32.1 (7.0 g,16.50mmol,1 eq) was suspended in 2-MeTHF (150 mL) and 4- (trifluoromethyl) phenylboronic acid (5.640 g,29.7mmol,1.8 eq), K was added 2 CO 3 (4.65g，33mmol，2eq)、H 2 O(15ml)、Pd(dppf)Cl 2 DCM (269.5 mg,0.33mmol,0.02 eq). Vac-Fill Argon was cycled 3 times and the resulting mixture was stirred and heated at 95℃for 12 hours under an Argon atmosphere, the mixture was cooled to room temperature, 1N HCl (20 ml) was added and stirred for 15 minutes and then held at room temperature for 1 hour. The solid was filtered, stirred with DMF at room temperature for 15 min, then filtered, the greenish-yellow solid was washed with MeOH, then dried in a vacuum oven to give 6.70g greenish-yellow solid, which was used in the next step without further purification. 83% yield. MS (APCI): c (C) 27 H 14 F 3 NO 5 Calculated value of (M-) =489; actual measurement value: 489. 1 H NMR(400MHz,DMSO-d 6 )δ8.52(s,1H),8.37(q,J＝8.1,7.7Hz,3H),8.04(d,J＝7.9Hz,2H),7.93(d,J＝8.7Hz,1H),7.84(d,J＝8.0Hz,2H),7.49(d,J＝8.6Hz,1H),7.34(d,J＝8.3Hz,1H),4.67(s,2H)。
compound PLC-33
General procedure for Compound PLC-33: PLC-33.1 (73.4 mg,0.15mmol,1.5 eq) was suspended in anhydrous DCM (10.0 ml), and PLC-2.1 (58.5 mg,0.1mmol,1 eq), DMAP were added pTSA (58.8 mg,0.2mmol,2 eq), EDC.HCl (57.5 mg,0.3mmol,3 eq), stirred at room temperature under argon atmosphere for 5 hours, diluted with DCM (150 ml), filtered, the solid washed with 50ml DCM, the filtrate collected and loaded to 80g SiO 2 On the column, eluting with Hex-DCM (1/1), DCM only, then 0.5% EA in DCM, collecting the pure fractions, concentrating, washing with hot MeOH to give 82mg of a dark purple solid in 77% yield. MS (APCI): the chemical formula: c (C) 60 H 37 BCl 2 F 5 N 3 O 5 Calculated value of (M-) =1055; actual measurement value: 1055. 1 H NMR(400MHz,d 2 -TCE)δ8.66(d,J＝7.9Hz,1H),8.61(d,J＝8.4Hz,1H),8.21(d,J＝2.2Hz,1H),8.04(d,J＝8.1Hz,1H),7.96(s,2H),7.73(dd,J＝9.7,1.8Hz,H),7.47(d,J＝8.6Hz,1H),7.38(s,1H),7.35(d,J＝8.4Hz,1H),7.27(dt,J＝7.3,3.7Hz,3H),7.23-7.16(m,2H),6.35(s,2H),5.19(s,2H),2.53(d,J＝7.4Hz,4H),2.22(s,4H),2.03-1.86(m,4H)。
synthesis procedure of Compound PLC-34
General procedure for Compound PLC-34.1: ex-4.3 (1.223 g,3.33mmol,1 eq) was suspended in 35mL anhydrous DMSO and 5-amino-1-pentanol (0.687 g,6.66mmol,2 eq) was added to the reaction mixture at room temperature. The resulting mixture was stirred at 160 ℃ for 45 minutes, LMCMS showed the reaction was complete. After cooling to room temperature, the solid product was filtered, washed with water (250 mL), then MeOH (100 mL) and dried in a vacuum oven to give 1.2g of a greenish yellow solid in 85% yield. MS (APCI): c (C) 23 H 18 BrNO 4 Calculated value of (M-) =453; actual measurement value: 453. 1 H NMR(400MHz,d 2 -TCE)δ8.52(d,J＝7.8Hz,1H),8.48(d,J＝8.3Hz,1H),8.09(d,J＝2.3Hz,1H),7.82(d,J＝8.0Hz,1H),7.54(dd,J＝8.8,2.3Hz,1H),7.23(d,J＝8.3Hz,1H),7.19(d,J＝8.8Hz,1H),4.14-4.02(m,2H),3.64-3.49(m,2H),1.68(p,J＝7.7Hz,2H),1.60-1.54(m,2H),1.41(q,J＝8.0Hz,2H),1.28(s,1H)。
general procedure for Compound PLC-34.2: PLC-34.1 (1.13 g,2.5mmol,1 eq) in DMF (10 ml), H 2 O (5 ml) was added 4- (trifluoromethyl) phenylboronic acid (0.949 g,5.0mmol,2 eq), K 2 CO 3 (0.691g，5.0mmol，2eq)、Pd(dppf)Cl 2 DCM (40.8 mg,0.05mmol,0.02 eq). The mixture was degassed 3 times by Vac-Fill Argon cycle, stirred and heated at 90℃for 5 hours. The reaction mixture was cooled to room temperature and water was added. The resulting mixture was kept at room temperature for 12 hours. The green-yellow solid was filtered, washed with water, then MeOH to give 1.24g of green-yellow solid in 95% yield. MS (APCI): c (C) 30 H 22 F 3 NO 4 Calculated value of (M-) =517; actual measurement value: 517. 1 H NMR(400MHz,d 2 -TCE)δ8.56(d,J＝7.9Hz,1H),8.51(d,J＝8.3Hz,1H),8.17(d,J＝2.1Hz,1H),7.97(d,J＝8.0Hz,1H),7.69(dd,J＝10.3,1.9Hz,4H),7.42(d,J＝8.6Hz,1H),7.28(d,J＝8.3Hz,1H),4.09(t,J＝7.5Hz,2H),3.57(q,J＝6.2Hz,2H),1.69(p,J＝7.8Hz,2H),1.61-1.54(m,2H),1.42(q,J＝8.0Hz,2H),1.28(t,J＝5.5Hz,1H)。
general procedure for Compound PLC-34.3: a mixture of PLC-34.2 (0.66 g, 1.284 mmol) and 48% aqueous HBr (20.0 ml) was refluxed (HBr 48% bp:126 ℃) by a heated block at 120℃for 5 hours under stirring. After cooling to room temperature, the mixture was poured into ice water, the solid was filtered, washed with water and dried in a vacuum oven to give 82% of the desired compound containing unreacted SM. 0.7g of a greenish-yellow solid is obtained in 93% yield. The product was used in the next step without further purification. MS (APCI): c (C) 30 H 21 BrF 3 NO 3 Calculated value of (M-) 581; actual measurement value: 581. 1 H NMR(400MHz,d 2 -TCE)δ8.57(d,J＝7.9Hz,1H),8.51(d,J＝8.3Hz,1H),8.18(d,J＝2.2Hz,1H),7.98(d,J＝7.9Hz,1H),7.69(dd,J＝9.6,2.0Hz,4H),7.43(d,J＝8.6Hz,1H),7.28(d,J＝8.3Hz,1H),4.09(t,J＝7.5Hz,3H),3.38(t,J＝6.7Hz,2H),1.97-1.81(m,2H),1.69(t,J＝7.8Hz,2H)。
compound PLC-34
General procedure for Compound PLC-34: PLC-34.3 (87.06 mg,0.15mmol,1.5 eq) was suspended in anhydrous DMF (10.0 ml) and PLC-2.1 (63.65 mg,0.10 m) was added mol，1eq)、K 2 CO 3 (41.46 mg,0.3mmol,2 eq), naI (8.3 mg, catalytic amount). The resulting mixture was stirred at 65 ℃ under argon atmosphere for 15 hours, cooled to room temperature, the solid filtered and washed with 50mL of water; the crude product was loaded onto a 40g silica gel column eluting with Hex: DCM (9:1) to DCM to give 75mg of a reddish brown solid in 69%. MS (APCI): c (C) 63 H 45 BCl 2 F 5 N 3 O 4 Calculated value of (M-) =1083; actual measurement value: 1083. 1 H NMR(400MHz,d 2 -TCE)δ8.59(d,J＝7.9Hz,1H),8.54(d,J＝8.3Hz,1H),8.18(d,J＝2.1Hz,1H),8.00(d,J＝8.1Hz,1H),7.96(s,1H),7.70(dd,J＝7.4,2.2Hz,3H),7.43(d,J＝8.6Hz,1H),7.30(d,J＝8.3Hz,1H),7.29-7.25(m,2H),7.22-7.19(m,1H),6.98(s,2H),6.39(s,2H),4.15(t,J＝7.5Hz,2H),3.99(t,J＝6.2Hz,2H),2.55(t,J＝6.6Hz,2H),2.23(s,2H),1.98-1.92(m,2H),1.86(s,1H),1.77(s,1H),1.58(s,2H)。
synthesis procedure of Compound PLC-35
Compound PLC-35.1- (9-bromo-2- (2- (2-hydroxyethoxy) ethyl) -1H-xantho [2,1,9-def]General procedure for isoquinoline-1, 3 (2H) -dione: a100 mL flask was equipped with a stir bar. Into the flask, ex-4.3 (1.5 g,4.1 mmol), 2- (2-aminoethoxy) ethan-1-ol (859.0 mg,8.2 mmol) and DMAP (35.1 mg,0.3 mmol) in DMF (30 ml) were degassed at room temperature. The reaction mixture was heated to 165 ℃ and the reaction was maintained at that temperature for 2 hours. TLC and LCMS showed the reaction was complete. The reaction was cooled to room temperature. Adding H 2 O (70 ml) to precipitate the product. The precipitate was collected by filtration. The solid was treated with H 2 O (150 ml) was washed and dried further in a vacuum oven at 100deg.C for 3 hours to give PLC-35.1 as a yellow solid which was used in the next step without further purification. 1.45g,78% yield. MS (APCI): c (C) 22 H 16 BrNO 5 ([M-H] - ) Calculated = 454, measured: 454. 1 H NMR(400MHz,CDCl 2 CDCl 2 )8.62(d,J＝8.0Hz,1H),8.59(d,J＝8.0Hz,1H),8.19(d,J＝2.4Hz,1H),7.92(d,J＝8.0Hz,1H),7.65(dd,J＝8.0Hz,J＝2.4Hz,2H),7.33(d,J＝8.0Hz,1H),7.29(d,J＝8.0Hz,1H),4.42(t,J＝5.6Hz,2H),3.85(t,J＝5.6Hz,2H),3.67(m,4H)。
compound PLC-35.2- (2- (2- (2-hydroxyethoxy) ethyl) -9- (4- (trifluoromethyl) phenyl) -1H-xantho [2,1,9-def]General procedure for isoquinoline-1, 3 (2H) -dione: the 250mL flask was fitted with a stir bar. Into a flask, the flask was filled with THF/DMF/H 2 PLC-35.1 (800.0 mg,1.8 mmol), 4- (trifluoromethyl) phenylboronic acid (670.0 mg,3.5 mmol), pd (dppf) Cl in O (48 ml/9.6ml/4.8 ml) 2 (90.6 mg,0.1 mmol) and K 2 CO 3 (659.5 mg,4.8 mmol) was degassed at room temperature. The reaction mixture was heated to 80 ℃ and the reaction was maintained at that temperature overnight. TLC was used to monitor the reaction. After completion, by adding H 2 O (150 ml) was treated to precipitate the product. The precipitate was collected by filtration. The solid was treated with H 2 O (200 ml) and MeOH (20 ml) were washed and further dried in a vacuum oven at 100deg.C for 3 hours to give PLC-35.2 as a yellowish green solid which was used in the next step without further purification. Quantitative yield. MS (APCI): c (C) 29 H 20 F 3 NO 5 ([M+H] + ) Calculated value of = 520, measured value: 520. 1 H NMR(400MHz,CDCl 2 CDCl 2 )8.67(d,J＝8.0Hz,1H),8.61(d,J＝8.0Hz,1H),8.26(d,J＝2.0Hz,1H),8.07(d,J＝8.0Hz,1H),7.79(m,5H),7.52(d,J＝8.4Hz,1H),7.38(d,J＝8.4Hz,1H),5.11(bs,1H),4.44(t,J＝1.6Hz,2H),3.86(t,J＝1.6Hz,2H),3.68(m,4H)。
compounds PLC-35.3A and PLC-35.3B- (methanesulfonic acid 2- (2- (1, 3-dioxo-9- (4- (trifluoromethyl) phenyl) -1H-xanthene-o [2,1, 9-def)]Isoquinolin-2 (3H) -yl) ethoxy) ethyl ester and 2- (2- (2-chloroethoxy) ethyl) -9- (4- (trifluoromethyl) phenyl) -1H-xantho [2,1,9-def ]General procedure for isoquinoline-1, 3 (2H) -dione: a100 mL flask was equipped with a stir bar. To the flask were added PLC-35.2 (900.0 mg,1.7 mmol) and DMF/THF (18 ml/6 ml). The solution was degassed at room temperature. Methanesulfonyl chloride (595.4 mg,5.2 mmol) and TEA (526.2 mg,5.2 mmol) were added. The solution was then heated to 90℃And kept at that temperature for 20 minutes. TLC was used to monitor the reaction. After completion, by adding H 2 O (150 ml) was treated to precipitate the product. The precipitate was collected by filtration. The solid was treated with H 2 O (100 ml) and MeOH (15 ml) were washed and further dried in a vacuum oven at 100deg.C for 3 hours to give a mixture of PLC-35.3A and PLC-35.3B (-1:1 molar ratio) as a yellow solid which was used in the next step without further purification. Quantitative yield. For PLC-35.4A, MS (APCI): c (C) 30 H 22 F 3 NO 7 S([M+H] + ) Calculated = 598, found: 598. 1 H NMR(400MHz,CDCl 2 CDCl 2 ) 8.65 (d, j=8.0 hz, 1H), 8.60 (d, j=8.0 hz, 1H), 8.26 (d, j=2.0 hz, 1H), 8.07 (d, j=8.0 hz, 1H), 7.78 (m, 5H), 7.52 (d, j=8.4 hz, 1H), 7.38 (d, j=8.4 hz, 1H), 4.44 (t, j=2.0 hz, 2H), 4.35 (m, 2H), 3.86 (t, j=2.0 hz, 2H), 3.81 (m, 2H), 3.01 (s, 3H). For PLC-35.4B, MS (APCI): c (C) 29 H 19 ClF 3 NO 4 ([M-H] - ) Calculated = 537, found: 537. 1 H NMR(400MHz,CDCl 2 CDCl 2 )8.66(d,J＝8.0Hz,1H),8.61(d,J＝8.0Hz,1H),8.26(d,J＝2.0Hz,1H),8.07(d,J＝8.0Hz,1H),7.79(m,5H),7.52(d,J＝8.4Hz,1H),7.37(d,J＝8.4Hz,1H),4.43(t,J＝2.0Hz,2H),3.86(t,J＝2.0Hz,2H),3.81(t,J＝1.6Hz,2H),3.63(t,J＝1.6Hz,2H)。
Compound PLC-35.4- (2, 6-dichloro-4- (2- (2- (1, 3-dioxo-9- (4- (trifluoromethyl) phenyl) -1H-xantho [2,1, 9-def)]Isoquinoline-2 (3H) -yl) ethoxy) benzaldehyde) general procedure: to a 100ml flask, naH (69.1 mg,2.9 mmol) and DMF (20 ml) were added followed by 4-hydroxy-2, 6-dichlorobenzaldehyde (413.3 mg,2.2 mmol). The mixture was kept stirring for 10 minutes at room temperature. A mixture of PLC-35.3A (0.7 mmol) and PLC-35.3B (0.7 mmol) was added (862.0 mg,1.4mmol total). The reaction was heated to 160 ℃ and kept stirring overnight at that temperature. TLC (50% etoac in hexanes) showed the reaction was complete. The reaction mixture was purified by flash chromatography on silica gel using EtOAc (0-40%) in DCM as eluent to give pure compound PLC-35.4 as a yellow solid, 580.0mg,60% yield. MS (APCI): c (C) 36 H 22 Cl 2 F 3 NO 6 ([M-H] - ) Calculated value of (1) =691, found: 691. 1 H NMR(400MHz,CDCl 2 CDCl 2 )δ10.06(s,1H),8.60(d,J＝8.0Hz,1H),8.57(d,J＝8.0Hz,1H),8.24(d,J＝2.0Hz,1H),8.02(d,J＝8.0Hz,1H),7.81(m,5H),7.52(d,J＝8.0Hz,1H),7.34(d,J＝8.0Hz,1H),6.56(s,2H),4.44(t,J＝2.0Hz,2H),3.98(m,2H),3.93(t,J＝2.0Hz,2H),3.86(m,2H)。
compound PLC-35- (2- (2- (2- (3, 5-dichloro-4- (19, 19-difluoro-6,7,11,12,13,19-hexahydro-5H-18 l4,19l 4-benzo [3',4 ') ] ']Cyclohepta [1',2':4,5]Pyrrolo [1,2-c]Benzo [3',4 ]']Cyclohepta [1',2':4,5]Pyrrolo [2,1-f][1,3,2]Diazaborane-9-yl) phenoxy) ethoxy) ethyl) -9- (4- (trifluoromethyl) phenyl) -1H-xantho [2,1,9-def ]General procedure for isoquinoline-1, 3 (2H) -dione: a 100mL 2-neck round bottom flask was fitted with an air condenser and a stirrer bar. To the flask were added PLC-35.4 (140.0 mg,0.2 mmol) and Ex-7.3 (77.7 mg,0.4 mmol), followed by anhydrous dichloromethane (4 ml). The reaction mixture was bubbled with Ar for 30 min, then p-TsOH H was added 2 O (1.2 mg,0.01 mmol). The reaction solution was kept at this temperature for 2 hours. DDQ (25.0 mg,0.1 mmol) was then added. The reaction was kept at room temperature for 30 minutes. BF was then added at room temperature 3 ·OET 2 (0.3 mL,2.4 mmol) and Et 3 N (0.2 mL,1.6 mmol). The reaction mixture was kept at room temperature overnight. The reaction mixture was loaded with silica gel and purified by flash chromatography using EtOAc (0-5%) in DCM as eluent to give pure PLC-35 as a dark purple solid, 121.0mg,55% yield. MS (APCI): c (C) 62 H 43 BCl 2 F 5 N 3 O 5 ([M-H] - ) Calculated = 1086, found: 1086. 1 H NMR(400MHz,CDCl 2 CDCl 2 )8.69(d,J＝8.0Hz,1H),8.63(d,J＝8.0Hz,1H),8.26(d,J＝2.4Hz,1H),8.08(d,J＝8.0Hz,1H),8.04(m,2H),7.78(m,5H),7.51(d,J＝8.0Hz,1H),7.34(m,7H),6.99(s,2H),6.44(s,2H),4.49(t,J＝2.0Hz,2H),4.18(m,2H),3.96(m,4H),2.63(m,4H),2.31(bs,4H),2.04(m,4H)。
synthesis procedure of Compound PLC-36
Compound PLC-36.5- (2- (4- (9-bromo-1, 3-dioxo-1H-xantheno [2,1, 9-def)]General procedure for isoquinolin-2 (3H) -yl) phenyl) acetic acid: a 100mL 2N round bottom flask was placed in an aluminum heating block and charged to a stir bar. The flask was fitted with a fin-type condenser/gas connector and a flow control valve. The system was purged with argon. To the flask were added Ex-4.3 (0.702 mmol,250 mg), 2- (4-aminophenyl) acetic acid (1.754 mmol,265 mg) and DMAP (0.0512 mmol,6.3 mg) followed by anhydrous DMF (10 mL). The reaction mixture was stirred under argon and the heating block was set to 170 ℃. The reaction mixture was stirred at 170 ℃ for 9 hours and then at room temperature. The crude reaction mixture was diluted with 75mL of water. The mixture was stirred for 5 minutes, then the crude product was filtered off and dried by suction for 5 minutes. The wet precipitate was dried in a vacuum oven at about 110 ℃ overnight. A pale yellow powder was obtained, 366mg (107% yield). NMR showed about 10-15% of the dimethylamide byproduct. MS (APCI): c (C) 26 H 14 BrNO 5 ([M+H] + ) Calculated value of =500; actual measurement value: 500. 1 H NMR(400MHz,DMSO-d 6 )δ8.60(d,J＝2.3Hz,1H),8.49-8.45(m,2H),8.39(d,J＝8.1Hz,1H),7.80-7.75(m,1H),7.48-7.43(m,2H),7.43-7.38(m,2H),7.31-7.27(m,2H),3.67(s,2H)。
general procedure for compound PLC-36.2- (2- (4- (2- (2- (2-methoxyethoxy) ethoxy) phenyl) -4, 5-tetramethyl-1, 3, 2-dioxaborolan): a 250mL 2N round bottom flask was placed in an aluminum heating block and charged to a stir bar. The flask was fitted with a fin-type condenser/gas connector and a flow control valve. The system was purged with argon. To the flask was added 4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenol (11.0 mmol, 2.426 g), 1-bromo-2- (2- (2-methoxyethoxy) ethoxy) ethane (10.0 mmol,2.48 mL), anhydrous DMF (25 mL) and K 2 CO 3 (11.0 mmol,1.520 g). The reaction mixture was stirred under argon atmosphere at room temperature for 5 minutes, then the heating block was set at 50℃and the reaction was allowed to proceedThe mixture should be stirred at 50 ℃ for 6 hours and then at room temperature over the weekend. The reaction mixture was diluted with water (. About.200 mL) and then extracted with diethyl ether (3X 100 mL). The combined ether layers were treated with saturated NaHCO 3 Aqueous (50 mL), brine (50 mL) washing over MgSO 4 Dried, filtered and evaporated to dryness in vacuo. A pale yellow oil (4.166 g,114% yield) was obtained. NMR indicated it as a mixture of the desired product and starting bromo-ethylene glycol, estimated to be about 57% product. Used in the next step without further purification. MS (APCI): c (C) 19 H 31 BO 6 ([M+H]Calculated value of +) 367; actual measurement value: 367. 1 h NMR (400 MHz, methanol-d) 4 )δ7.69-7.63(m,2H),6.95-6.90(m,2H),4.18-4.11(m,2H),3.86-3.82(m,2H),3.72-3.67(m,2H),3.66-3.60(m,2H),3.54-3.48(m,4H),3.34(s,3H)。
Compound PLC-36.3- (2- (4- (2- (2- (2-methoxyethoxy) ethoxy) phenyl) -1, 3-dioxo-1H-xantheno [2,1, 9-def)]General procedure for isoquinolin-2 (3H) -yl) phenyl) acetic acid: a 250mL 2N round bottom flask was placed in an aluminum heating block and charged to a stir bar. The flask was fitted with a fin-type condenser/gas connector and a flow control valve. The system was purged with argon. To the flask were added PLC-36.1 (2.00 mmol,1001 mg), PLC-36.2 (4.00 mmol,1465 mg), K 2 CO 3 (5.50 mmol,760 mg) and Pd (dppf) Cl 2 (0.140 mmol,102 mg) followed by THF (60 mL), DMF (12 mL) and water (6 mL). The reaction mixture was stirred under argon and bubbled with nitrogen for 10 minutes. The nitrogen sparge was stopped and stirring continued under argon. The heating block was set at 80 ℃ for 2 hours. The reaction mixture was quenched with 6N HCl (5 mL) and diluted with water (50 mL) and THF (50 mL). Sodium chloride was added until the aqueous layer was saturated, then the layers were separated, and the aqueous layer was extracted with THF (3×50 mL). The combined organic layers were washed with brine (50 mL), and dried over MgSO 4 Dried, filtered, and evaporated to dryness in vacuo (including DMF). The crude product was evaporated onto-50 g of flash silica gel and placed in a loader. Purification by silica gel flash chromatography (220 g, solid loading, equilibration of 100% DCM, elution of 100% DCM (2 CV) →40% (EtOAc/0.1% TFA)/DCM (20 CV) →70% (EtOAc/0.1% TF A)/DCM (20 CV)). Will contain the product Is evaporated to dryness in vacuo. A yellow solid, 722mg (55% yield) was obtained. MS (APCI): c (C) 39 H 33 NO 9 ([M+H]Calculated value of +) =660; actual measurement value: 660. 1 H NMR(400MHz,DMSO-d 6 )δ8.57(d,J＝2.2Hz,1H),8.52(s,2H),8.48(d,J＝8.3Hz,1H),7.90(dd,J＝8.7,2.2Hz,1H),7.84-7.78(m,2H),7.55(d,J＝8.7Hz,1H),7.48(d,J＝8.3Hz,1H),7.41(d,J＝8.1Hz,2H),7.33-7.26(m,2H),7.12-7.07(m,2H),4.22-4.14(m,2H),3.82-3.76(m,2H),3.68(s,2H),3.65-3.59(m,2H),3.58-3.51(m,4H),3.48-3.41(m,2H),3.25(s,3H)。
compound PLC-36- (3, 5-dichloro-4- (19, 19-difluoro-6,7,11,12,13,19-hexahydro-5H-18 l4,19l 4-benzo [3',4 ]']Cyclohepta [1',2':4,5]Pyrrolo [1,2-c]Benzo [3',4 ]']Cyclohepta [1',2':4,5]Pyrrolo [2,1-f][1,3,2]Diazaborane-9-yl) phenyl 2- (4- (9- (4- (2- (2- (2-methoxyethoxy) ethoxy) phenyl) -1, 3-dioxo-1H-xantheno [2,1,9-def]General procedure for isoquinolin-2 (3H) -yl) phenyl) acetate: a40 mL vial was filled with stirring rod, followed by PLC-2.1-3, 5-dichloro-4- (19, 19-difluoro-6,7,11,12,13,19-hexahydro-5H-18 l4,19l 4-benzo [3',4 ]']Cyclohepta [1',2':4,5]Pyrrolo [1,2-c]Benzo [3',4 ]']Cyclohepta [1',2':4,5]Pyrrolo [2,1-f][1,3,2]Diazaborane-9-yl) phenol (0.050 mmol,29.3 mg), PLC-36.3 (0.075 mmol,49.5 mg), DMAP. PTsOH salt (0.100 mmol,29.4 mg) and EDC. HCl (0.300 mmol,29 mg) were then charged into anhydrous DCM. The vials were capped and the reaction mixture was stirred at room temperature overnight. The crude reaction was quenched with a few drops of TFA and loaded onto-65 g of flash silica in a cartridge. Purification was by flash chromatography on silica gel (120 g, solid loading, equilibration of 100% DCM, elution of 100% DCM (3 CV) →5.8% etoac/DCM (11.6 CV) →13.3% etoac/DCM (6.0 CV) →50% etoac/DCM (10 CV)). The product-containing fractions were evaporated to dryness in vacuo. The crude product was triturated with hot methanol. The product was filtered off, dried by suction and then dried in a vacuum oven at-110 ℃. A dark red solid, 47.1mg (77% yield) was obtained. MS (APCI): c (C) 72 H 56 BCl 2 F 2 N 3 O 9 Calculated value of (M-) =1225; actual measurement value: 1225. 1 h NMR (400 MHz, tetrachloroethane-d) 2 )δ8.68(d,J＝7.8Hz,1H),8.63(d,J＝8.3Hz,1H),8.25(d,J＝2.1Hz,1H),8.11(d,J＝8.1Hz,1H),8.09-8.00(m,2H),7.78(dd,J＝8.6,2.1Hz,1H),7.69-7.61(m,4H),7.50(d,J＝8.6Hz,1H),7.46-7.34(m,9H),7.33-7.26(m,2H),7.14-7.05(m,2H),6.48(s,2H),4.22(t,J＝4.7Hz,2H),4.07(s,2H),3.94-3.88(m,2H),3.78-3.72(m,2H),3.72-3.62(m,4H),3.59-3.53(m,2H),3.38(s,3H),2.64(t,J＝6.8Hz,4H),2.44-2.22(m,4H),2.12-1.97(m,4H)。
Synthesis procedure of Compound PLC-37
Compound PLC-37.1- (9-bromo-2- (2-hydroxyethyl) -1H-xantheno [2,1,9-def]General procedure for isoquinoline-1, 3 (2H) -dione: a 50mL 2N round bottom flask was placed in an aluminum heating block and charged to a stir bar. The flask was fitted with a fin-type condenser/gas connector, plug and flow control valve. The system was purged with argon. To the flask were added Ex-4.3 (3.00 mmol, 1100 mg), ethanolamine (12.0 mmol, 0.720 mL) and DMAP (0.900 mmol,110 mg), followed by anhydrous DMF (8 mL). The reaction mixture was stirred under argon and the heating block was set to 165 ℃. The reaction mixture was stirred at this temperature for 3 hours, and then the reaction mixture was cooled to room temperature. The solvent was evaporated to dryness in vacuo. The residue was triturated with water (50 mL) and 6N aqueous HCl (10 mL). The mixture was sonicated for several minutes, then stirred at room temperature for 30 minutes, then the solid product was filtered off and washed with water. The crude filter cake was dried overnight in a vacuum oven at-110 ℃. A dark brown solid was obtained, 1.038 (84% yield). MS (APCI): c (C) 20 H 12 BrNO 4 Calculated value of (m+h) =410; actual measurement value: 410.
Compound PLC-37.2- (2- (2-hydroxyethyl) -9- (4- (trifluoromethyl) phenyl) -1H-xantho [2,1,9-def]General procedure for isoquinoline-1, 3 (2H) -dione: in a similar manner to PLC-36.7, from the solution in THF/DMF/H 2 PLC-37.1 (2.531 mmol,1.038 g), (4- (trifluoromethyl) phenyl) boronic acid (5.062 mmol,961 mg), K in O (60 mL/12mL/6 mL) 2 CO 3 (6.960 mmol,962 mg) and Pd (dppf) Cl 2 (0.177 mmol,130 mg) at 80℃for 30 min. The crude product was precipitated by the addition of water (100 mL) and the resulting solid was filtered off and washed with water. The crude product was triturated with methanol and then dried overnight in a vacuum oven at-110 ℃. 1.017g (84% yield) was obtained. MS (APCI): c (C) 27 H 16 F 3 NO 4 Calculated value of (m+h) =476; actual measurement value: 476. 1 H NMR(400MHz,TCE)δ8.66(d,J＝7.8Hz,1H),8.61(d,J＝8.3Hz,1H),8.25(d,J＝2.2Hz,1H),8.06(d,J＝8.0Hz,1H),7.83-7.75(m,5H),7.52(d,J＝8.6Hz,1H),7.37(d,J＝8.4Hz,1H),4.45(t,J＝5.2Hz,2H),3.98(q,J＝5.3Hz,2H),2.49(t,J＝5.5Hz,1H)。
compound PLC-37.3- (2- (2-chloroethyl) -9- (4- (trifluoromethyl) phenyl) -1H-xantho [2,1,9-def]General procedure for isoquinoline-1, 3 (2H) -dione: a 250mL 2N round bottom flask was placed in an aluminum heating block and charged to a stir bar. The flask was fitted with a fin-type condenser/gas connector, plug and flow control valve. The system was purged with argon. Into the flask were added PLC-37.2 (2.124 mmol,1.01 g), pTsCl (6.372 mmol,1.215 g), anhydrous DMF (20 mL) and Et 3 N (6.372 mmol,0.888 mL). The reaction mixture was stirred under argon and heated to 80 ℃ for 2 hours. When the tosylate is replaced in situ with chloride, an undesired reaction occurs. The reaction mixture was cooled to room temperature and diluted with water (100 mL). The crude product is filtered off and washed with water. The crude product was triturated with methanol. The product was dried overnight in a vacuum oven at-110 ℃. 974mg of an orange solid was obtained (93% yield). MS (APCI): c (C) 27 H 15 ClF 3 NO 3 Calculated value of (m+h) =494; actual measurement value: 494. 1 H NMR(400MHz,TCE)δ8.67(d,J＝7.9Hz,1H),8.62(d,J＝8.3Hz,1H),8.27(d,J＝2.2Hz,1H),8.08(d,J＝7.9Hz,1H),7.86-7.73(m,5H),7.53(d,J＝8.6Hz,1H),7.39(d,J＝8.4Hz,1H),4.56(t,J＝6.9Hz,2H),3.87(t,J＝6.8Hz,2H)。
compound PLC-37.4- (2, 6-dichloro-4- (2- (1, 3-dioxo-9- (4- (trifluoromethyl) phenyl) -1H-xantho [2,1, 9-def)]Isoquinoline-2 (3H) -yl) ethoxy) benzaldehyde): a 100mL 2N round bottom flask was placed in an aluminum heating block and charged to a stir bar. The flask was fitted withA fin-type condenser/gas connector, a plug, and a flow control valve. The system was purged with argon. To the flask was added NaH (60% in mineral oil) (1.214 mmol,29.1mg,60%,49 mg) followed by anhydrous DMF (20 mL). To the flask was added 2, 6-dichloro-4-hydroxybenzaldehyde (1.8231 mmol,348 mg). The reaction mixture was stirred under argon and the heating block was set to 50 ℃. The reaction was stirred at 50℃for 5 min, then PLC-37.3 (0.607 mmol,300 mg) was added. The flask was stoppered and stirred under argon. The heating block temperature was raised to 160 ℃. The reaction mixture was stirred at 160 ℃ for 90 minutes and then at room temperature overnight. The crude product was precipitated by the addition of water (100 mL) and the product was filtered off and washed with water. The crude product was dissolved in DCM and evaporated to dryness in vacuo. The crude product was evaporated in vacuo onto flash silica (20 g). Purification was by flash chromatography on silica gel (120 g, solid loading, equilibration of 100% DCM/hexane, elution of 100% DCM/hexane (7 CV) →0% EtOAc/DCM (0 CV) →0% EtOAc/DCM (5 CV) →40% EtOAc/DCM (40 CV)). The product-containing fractions were evaporated to dryness in vacuo. 152mg (39% yield) of a yellow solid was obtained. MS (APCI): c (C) 34 H 18 Cl 2 F 3 NO 5 Calculated value of (M-) =647; actual measurement value: 647. 1 H NMR(400MHz,TCE)δ10.36(s,1H),8.68(d,J＝7.9Hz,1H),8.63(d,J＝8.3Hz,1H),8.26(d,J＝2.1Hz,1H),8.07(d,J＝8.0Hz,1H),7.85-7.72(m,5H),7.52(d,J＝8.6Hz,1H),7.39(d,J＝8.4Hz,1H),6.99(s,2H),6.93(s,1H),4.65(t,J＝6.1Hz,2H),4.40(t,J＝6.1Hz,2H)。
compound PLC-37
Compound PLC-37- (2- (2- (3, 5-dichloro-4- (19, 19-difluoro-6,7,11,12,13,19-hexahydro-5H-18 l4,19l 4-benzo [3',4 ]']Cyclohepta [1',2':4,5]Pyrrolo [1,2-c]Benzo [3',4 ]']Cyclohepta [1',2':4,5]Pyrrolo [2,1-f][1,3,2]Diazaborane-9-yl) phenoxy) ethyl) -9- (4- (trifluoromethyl) phenyl) -1H-xantho [2,1,9-def]General procedure for isoquinoline-1, 3 (2H) -dione: a 100mL 2N round bottom flask was placed in an aluminum heating block and charged to a stir bar. The flask was fitted with a fin-type condenser/gas connector, plug and flow control valve. The system was purged with argon. PLC-37.4 (0.075 mmol,49 mg) and Ex-7.3-1,4,5, 6-tetrahydro were added to the flaskBenzo [6,7]Cyclohepta [1,2-b ]]Pyrrole (0.1575 mmol,29 mg) was followed by the addition of anhydrous DCM (20 mL). The reaction mixture was bubbled with nitrogen for 10 minutes under an argon atmosphere. Several pTsOH.H 2 Small particles of O are collected on the end of the spatula and immersed in the reaction mixture. Stirring was continued and sparged with nitrogen for an additional 5 minutes. The nitrogen sparge was stopped and the reaction mixture was stirred at room temperature for 1 hour, at which time TLC showed complete conversion to the desired dipyrromethene. DDQ (0.1275 mmol,29 mg) was added to the flask and the reaction mixture was stirred at room temperature for 15 min. TLC indicated complete oxidation to dipyrromethene (dipyrromethene). Et is added to the flask 3 N (0.600 mmol,0.084 mL) and BF 3 .OEt 2 (0.900 mmol,0.111 mL). After 2 minutes the two reagents were added repeatedly, then the heating block was set to 50 ℃, and the reaction mixture was stirred under argon at that temperature for 2 hours. The crude BODIPY was loaded directly onto flash silica gel (25 g). Purification was performed by flash chromatography on silica gel (80 g, solid loading, equilibration of 80% DCM/hexane, elution of 80% DCM/hexane (2 CV), 100 DCM/hexane M (5 CV), isocratic 100% DCM/hexane (. About.25 CV), 100% DCM/hexane/0.5% EtOAc modifier (. About.10 CV)). The product eluted as a broad peak. The product-containing fractions were evaporated to dryness in vacuo. A dark red solid was obtained, 89mg (quantitative yield). MS (APCI): c (C) 60 H 39 BCl 2 F 5 N 3 O 4 Calculated value of (M-) =1041; actual measurement value: 1041. 1 H NMR(400MHz,TCE)δ8.72(d,J＝7.9Hz,1H),8.67(d,J＝8.4Hz,1H),8.27(d,J＝2.2Hz,1H),8.10(d,J＝8.1Hz,1H),8.04(dd,J＝5.8,3.5Hz,2H),7.84-7.75(m,5H),7.53(d,J＝8.6Hz,1H),7.41(d,J＝8.3Hz,1H),7.39-7.32(m,4H),7.32-7.25(m,2H),7.14(s,2H),4.70(t,J＝6.2Hz,2H),4.42(t,J＝6.2Hz,2H),2.62(t,J＝7.0Hz,4H),2.41-2.18(m,4H),2.11-1.93(m,4H)。
synthesis procedure of Compound PLC-38
PLC-38.1 (9-bromo-2- (3-hydroxypropyl) -1H-xantheno [2,1,9-def]Synthesis of isoquinoline-1, 3 (2H) -dione: ex-4.3 (1.223 g,3.33mmol,1 eq) was suspended in 35mL anhydrous DMSO and 3-amino-1-propanol (1.5 g,20.0mmol,6 eq) was added to the reaction mixture at room temperature. The resulting mixture was stirred at 160 ℃ for 45 minutes, LCMS showed the reaction was complete. After cooling to room temperature, the solid product was filtered, the solid was washed with water (250 mL), then MeOH (100 mL) and dried in a vacuum oven to give 1.2g of a greenish-yellow solid in 92% yield. MS (APCI): c (C) 23 H 18 BrNO 4 Calculated value of (M-) =425; actual measurement value: 425. 1 H NMR(400MHz)δ8.56(d,J＝7.9Hz,1H),8.52(d,J＝8.4Hz,1H),8.13(d,J＝2.3Hz,1H),7.86(d,J＝7.9Hz,1H),7.57(dd,J＝8.8,2.3Hz,1H),7.26(d,J＝8.4Hz,1H),7.22(d,J＝8.8Hz,1H),4.24(t,J＝6.1Hz,2H),3.48(q,J＝6.1Hz,2H),3.06(t,J＝6.9Hz,1H),1.95-1.83(m,2H)。
PLC-38.2 (2- (3-hydroxypropyl) -9- (4- (trifluoromethyl) phenyl) -1H-xantho [2,1,9-def]Synthesis of isoquinoline-1, 3 (2H) -dione: PLC-38.1 (1.06 g,2.5mmol,1 eq) was suspended in DMF (10 ml), H 2 O (5 ml) was added 4- (trifluoromethyl) phenylboronic acid (0.949 g,5.0mmol,2 eq), K 2 CO 3 (0.691g，5.0mmol，2eq)、Pd(dppf)Cl 2 DCM (40.8 mg,0.05mmol,0.02 eq). The mixture was degassed 3 times by Vac-Fill Argon cycle, stirred and heated at 90℃for 5 hours. The reaction mixture was cooled to room temperature and water was added. The resulting mixture was kept at room temperature for 12 hours. The green-yellow solid was filtered, washed with water, then MeOH to give 1.04g of green-yellow solid in 85% yield. MS (APCI): c (C) 30 H 22 F 3 NO 4 Calculated value of (M-) =517; actual measurement value: 517. 1 H NMR(400MHz)δ8.56(d,J＝7.9Hz,1H),8.51(d,J＝8.3Hz,1H),8.17(d,J＝2.1Hz,1H),7.97(d,J＝8.0Hz,1H),7.69(dd,J＝10.3,1.9Hz,4H),7.42(d,J＝8.6Hz,1H),7.28(d,J＝8.3Hz,1H),4.09(t,J＝7.5Hz,2H),3.57(q,J＝6.2Hz,2H),1.69(p,J＝7.8Hz,2H),1.61-1.54(m,2H),1.42(q,J＝8.0Hz,2H),1.28(t,J＝5.5Hz,1H)。
PLC-38.3 (2- (3-bromopropyl) -9- (4- (trifluoromethyl) phenyl) -1H-xantho [2,1,9-def]Synthesis of isoquinoline-1, 3 (2H) -dione: under stirringA mixture of PLC-38.2 (1.6 g,3.2 mmol) and 48% aqueous HBr (30.0 ml) was heated to reflux via a heated block at 130℃for 3 days. The same volume of 48% aqueous HBr was added 2 more times over the next 2 days, with a total of 90ml. After cooling to room temperature, the mixture was poured into ice water, the solid was filtered, washed with water and dried in a vacuum oven to give 82% of the desired compound containing unreacted SM. 1.7g of a greenish-yellow solid are obtained in 96% yield. The product was used in the next step without further purification. MS (APCI): c (C) 30 H 21 BrF 3 NO 3 Calculated value of (M-) =551; actual measurement value: 551. 1 H NMR(400MHz)δ8.55(d,J＝7.9Hz,1H),8.50(d,J＝8.4Hz,1H),8.15(d,J＝2.2Hz,1H),7.96(d,J＝8.0Hz,1H),7.70(s,5H),7.41(d,J＝8.6Hz,1H),7.27(d,J＝8.3Hz,1H),4.22(t,J＝7.1Hz,2H),3.45(t,J＝6.8Hz,2H),2.25(q,J＝6.9Hz,2H)。
PLC-38 (2- (3, 5-dichloro-4- (19, 19-difluoro-6,7,11,12,13,19-hexahydro-5H-18 l4,19l 4-benzo [3',4 ]']Cyclohepta [1',2':4,5]Pyrrolo [1,2-c]Benzo [3',4 ]']Cyclohepta [1',2':4,5]Pyrrolo [2,1-f][1,3,2]Diazaborane-9-yl) phenoxy) propyl) -9- (4- (trifluoromethyl) phenyl) -1H-xantho [2,1,9-def]Synthesis of isoquinoline-1, 3 (2H) -dione: PLC-38.3 (41.425 mg,0.075mmol,1.15 eq) was suspended in anhydrous DMF (2.0 ml), and PLC-2.1 (38.04 mg,0.065mmol,1 eq), K was added 2 CO 3 (0.73 mg,0.15mmol,2.3 eq), naI (4.15 mg). The resulting mixture was stirred at 85 ℃ under argon atmosphere for 16 hours, cooled to room temperature, the solid filtered and washed with 50ml of water; the crude product was loaded onto a 40g silica gel column eluting with Hex: DCM (9:1) to DCM to give 49mg of a dark purple solid in 71% yield. MS (APCI): c (C) 63 H 45 BCl 2 F 5 N 3 O 4 Calculated value of (M-) =1055; actual measurement value: 1055. 1 H NMR(400MHz,)δ8.60(d,J＝7.8Hz,1H),8.55(d,J＝8.3Hz,1H),8.18(d,J＝2.2Hz,1H),8.00(d,J＝8.1Hz,1H),7.95(d,J＝5.9Hz,2H),7.74-7.65(m,4H),7.44(d,J＝8.6Hz,1H),7.34-7.24(m,4H),7.24-7.14(m,2H),6.91(s,2H),6.38(s,2H),4.36(t,J＝6.9Hz,2H),4.13(t,J＝6.1Hz,2H),2.54(t,J＝6.7Hz,4H),2.28-2.19(m,4H),2.06-1.85(m,4H),0.78(d,J＝14.2Hz,2H)。
synthesis procedure of PLC-39
Compound 39.1: a mixture of compound Ex-4.4 (649 mg,1.23 mmol), 4- (trifluoromethyl) phenylboronic acid (467 mg,2.46 mmol), pd (dppf) Cl2 (45 mg,0.06 mmol), potassium carbonate (345 mg,2.5 mmol) in a cosolvent of THF/DMF/water (30 mL/6mL/3 mL) was degassed and then heated overnight at 80 ℃. The mixture was treated with 300mL of ethyl acetate and 50mL of 0.6N aqueous hydrochloric acid. The aqueous phase was extracted with ethyl acetate (150 mL. Times.3). The organic phase was collected and washed with brine (100 ml×2), dried over sodium sulfate, then dried loaded onto silica gel, and purified by flash chromatography using an eluent of DCM/EA (0% to 80% EA with 0.1% tfa). The main desired fraction was collected and the solvent was removed under reduced pressure to give a yellow solid (414 mg, 57% yield). 1 H NMR(400MHz,d2-TCE)δ8.55(dd,J＝18.1,8.1Hz,2H),8.16(d,J＝2.2Hz,1H),8.00(d,J＝8.1Hz,1H),7.68(dd,J＝8.6,2.1Hz,1H),7.66-7.59(m,2H),7.43(d,J＝8.6Hz,1H),7.32(tt,J＝8.2,4.2Hz,5H),7.20-7.13(m,2H),2.72(t,J＝7.6Hz,2H),2.39(t,J＝7.3Hz,2H),1.99(q,J＝7.4Hz,2H)。
Compound PLC-39: a mixture of PLC-1.3 (32 mg,0.0547 mmol), PLC-39.1 (48.7 mg,0.082 mmol), EDC. HCl (60 mg,0.31 mmol) and DMAP/p-TsOH (15 mg,0.05 mmol) in DCM (5 mL) was stirred at room temperature overnight. The resulting mixture was then loaded onto silica gel by using DCM/ethyl acetate (0%10% ethyl acetate). The main red fraction was collected and concentrated to 0.5mL under reduced pressure, then 10mL methanol was added. The resulting precipitate was filtered and dried in air to give a dark red solid (44 mg, 69% yield). 1H NMR (400 MHz, d 2-TCE) δ8.56 (dd, J=17.8, 8.1Hz, 2H), 8.16 (d, J=2.2 Hz, 1H), 7.99 (dd, J=19.8, 6.8Hz, 3H), 7.68 (dd, J=8.6, 2.1Hz, 1H), 7.66-7.59 (m, 2H), 7.44 (d, J=8.6 Hz, 1H)),7.41-7.35(m,2H),7.35-7.25(m,9H),7.22(dd,J＝8.7,4.2Hz,4H),6.40(s,2H),2.82(t,J＝7.5Hz,2H),2.67(t,J＝7.4Hz,2H),2.55(t,J＝6.7Hz,4H),2.24(bs,4H),2.14(q,J＝7.5Hz,2H),1.96(t,J＝7.1Hz,4H)。
Synthesis procedure of PLC-40
Compound 40.1: a mixture of 9-bromo-2- (3-hydroxypropyl) -1H-xantheno [2,1,9-def ] isoquinoline-1, 3 (2H) -dione (PLC-38.1, 330mg,0.778 mmol), (2, 4, 6-triisopropylphenyl) boronic acid (290 mg,1.17 mmol), pd (PPh 3) 4 (80 mg,0.069 mmol), K2CO3 (320 mg,2.32 mmol) in 1, 4-dioxane/DMF/water (15 mL/3mL/1.5 mL) was degassed and heated at 90℃for 24 hours. The resulting mixture was treated with water and ethyl acetate. The organic phase was collected and loaded onto silica gel, purified by flash chromatography using DCM/EA (0% to 40% EA) eluent. The desired fractions were collected and the solvent was removed under reduced pressure to give a yellow solid (210 mg, 49% yield). LCMS (APCI-): calculated for C36H37NO 4: 547.27; actual measurement value: 547.1H NMR (400 MHz, d 2-TCE) delta 8.60-8.48 (m, 2H), 7.93-7.76 (m, 2H), 7.45-7.24 (m, 3H), 6.99 (s, 2H), 4.25 (t, J=6.1 Hz, 2H), 4.01 (q, J=7.2 Hz, 2H), 3.47 (t, J=5.5 Hz, 2H), 2.88 (p, J=6.8 Hz, 1H), 2.65-2.43 (m, 2H), 1.89 (d, J=6.2 Hz, 2H), 1.24 (d, J=6.9 Hz, 6H), 1.03 (t, J=7.1 Hz, 12H).
Compound 40.2: to a solution of compound PLC-40.1 (210 mg, 0.284 mmol) in 20mL DCM at room temperature was added carbon tetrabromide (CBr 4 252mg,0.76 mmol), triphenylphosphine (203 mg,0.77 mmol). The whole was stirred for 30 minutes. TLC showed the reaction was complete. The mixture was loaded onto silica gel and purified by flash chromatography using hexane/DCM (0% to 100% DCM) eluent. The desired fractions were collected and concentrated under reduced pressure to give a yellow solid (100 mg, 43% yield). LCMS (apci+): calculated for C36H37BrNO3 (m+h): 610.19; actual measurement value: 610.1H NMR (400 MHz, d 2-TCE) δ8.52 (dd, J=8.1, 2.5Hz, 2H), 8.00-7.72 (m, 2H), 7.45-7.19 (m, 3H), 6.98 (s, 2H), 4.23 (t, J=7.0 Hz, 2H), 3.44 (t, J=6.8Hz,2H),3.01-2.80(m,1H),2.69-2.45(m,2H),2.26(q,J＝6.9Hz,2H),1.24(d,J＝6.9Hz,6H),1.03(t,J＝6.9Hz,12H)。
Compound 40: a mixture of compound PLC-40.2 (50 mg,0.082 mmol), PLC-1.3 (58.5 mg,0.10 mmol), K2CO3 (20.7 mg,0.15 mmol) in anhydrous DMF was sonicated for 3 min and then heated at 75deg.C under an argon atmosphere for 5 hours. The resulting mixture was diluted with 100mL of DCM, washed with 0.1N aqueous HCl (50 mL. Times.2), and concentrated over MgSO 4 Dried, concentrated to 50mL, then loaded onto silica gel, and purified by using DCM/EA (0%5% ea) by flash chromatography. The main desired fraction was collected, concentrated and triturated with methanol then filtered to give a dark red solid (70 mg, 76.6% yield). LCMS (APCI-): calculated for C69H60BCl2F2N3O 4: 1113.40; actual measurement value: 1113.1H NMR (400 MHz, d 2-TCE) delta 8.63-8.43 (m, 2H), 8.08-7.72 (m, 4H), 7.46-7.13 (m, 9H), 6.94 (d, J=31.3 Hz, 4H), 6.38 (s, 2H), 4.35 (t, J=6.8 Hz, 2H), 4.12 (t, J=5.9 Hz, 2H), 2.98-2.77 (m, 1H), 2.54 (q, J=6.8 Hz, 6H), 2.23 (d, J=6.0 Hz, 6H), 2.04-1.89 (m, 4H), 1.23 (d, J=6.9 Hz, 6H), 1.02 (dd, J=6.9, 3.5Hz, 6H).
Synthesis of Compound PLC-41
Synthesis of the Compound PLC-41.1- (9-bromo-2-hydroxybutyl) -1H-xantho [2,1,9-def]General procedure for isoquinoline-1, 3 (2H) -dione: the 100mL flask was fitted with a stir bar. Into the flask, compound Ex-4.3 (1.0 g,2.7 mmol), 4-aminobutan-1-ol (485.3 mg,5.4 mmol) and DMAP (23.1 mg,0.19 mmol) in DMF (20 ml) were degassed at room temperature. The reaction mixture was heated to 165 ℃ and the reaction was maintained at that temperature for 2.5 hours. TLC and LCMS showed the reaction was complete. The reaction was cooled to room temperature. Adding H 2 O (80 ml). The solid product was collected by vacuum filtration and purified by filtration with H 2 O (100 ml) and further dried in a vacuum oven at 100deg.CDrying for 3 hours gave PLC-41.1 as a brown solid which was used in the next step without further purification. 908.0mg,77% yield. MS (APCI): the chemical formula: C22H16BrNO4 ([ M-H)]Calculated = 438, found: 438.1H NMR (400 MHz, CDCl 2) 8.62 (d, J=8.0 Hz, 1H), 8.58 (d, J=8.0 Hz, 1H), 8.19 (d, J=2.4 Hz, 1H), 7.93 (d, J=8.0 Hz, 1H), 7.64 (dd, J=8.0 Hz, J=2.4 Hz, 2H), 7.32 (d, J=8.0 Hz, 1H), 7.28 (d, J=8.0 Hz, 1H), 4.20 (t, J=7.2 Hz, 2H), 3.83 (t, J=6.0 Hz, 2H), 1.82 (m, 2H), 1.69 (m, 2H).
Synthesis of Compound PLC-41.2- (2- (4-hydroxybutyl) -9- (4- (trifluoromethyl) phenyl) -1H-xantho [2,1, 9-def)]General procedure for isoquinoline-1, 3 (2H) -dione: the 250mL flask was fitted with a stir bar. Into a flask, THF/DMF/H 2 Compounds PLC-41.1 (900.0 mg,2.1 mmol), 4- (trifluoromethyl) phenylboronic acid (780.0 mg,4.1 mmol), pd (dppf) Cl2 (107.5 mg,0.15 mmol) and K2CO3 (782.5 mg,5.7 mmol) in O (60 ml/12ml/6 ml) were degassed at room temperature. The reaction mixture was heated to 80 ℃ and the reaction was maintained at that temperature overnight. TLC was used to monitor the reaction. After completion, by adding H 2 O (150 ml) was treated to precipitate the product. The precipitate was collected by filtration. The solid was treated with H 2 O (200 ml) and MeOH (20 ml) were washed and further dried in a vacuum oven at 100deg.C for 3 hours to give PLC-41.2 as a yellow solid which was used in the next step without further purification. 990.0mg,94% yield. MS (APCI): the chemical formula: C29H20F3NO4 ([ M+H)]Calculated +) = 504, found: 504.1H NMR (400 MHz, CDCl 2) 8.67 (d, J=8.0 Hz, 1H), 8.61 (d, J=8.0 Hz, 1H), 8.27 (d, J=2.4 Hz, 1H), 8.08 (d, J=8.0 Hz, 1H), 7.80 (m, 5H), 7.52 (d, J=8.4 Hz, 1H), 7.38 (d, J=8.4 Hz, 1H), 4.22 (t, J=7.2 Hz, 2H), 3.73 (t, J=6.0 Hz, 2H), 1.84 (m, 4H).
Synthesis of Compound PLC-41.3- (4- (1, 3-dioxo-9- (4- (trifluoromethyl) phenyl) -1H-xantho [2,1, 9-def)]General procedure for isoquinolin-2 (3H) -yl) butyl 4-methylbenzenesulfonate): a100 mL flask was equipped with a stir bar. To the flask were added compound PLC-41.2 (200.0 mg,0.40 mmol) and DCE (20 ml). The solution was degassed at room temperature. Para-toluenesulfonic anhydride (519.0 mg,1.6 mmol) and TEA (221.0. Mu.L, 1.6 mmol) were added. The solution is then subjected toHeated to 90 ℃ and held at that temperature for 4 hours. TLC and LCMS were used to monitor the reaction. More DCE (20 mL), p-toluenesulfonic anhydride (519.0 mg,1.6 mmol) was added. The reaction was cooled to room temperature. Adding H 2 O (100 ml), TEA (221.0. Mu.L, 1.6 mmol). The reaction was kept at 90℃overnight. After adding H 2 O (150 mL) to stop the reaction, the mixture was extracted with DCM (150 mL. Times.3). The combined organic phases were taken up in anhydrous Na 2 SO4 was dried and concentrated under vacuum rotary evaporator to give PLC-41.3 as a yellow solid which was used in the next step without further purification. MS (APCI): the chemical formula: C36H26F3NO6S ([ M-H)]Calculated = 657, found: 657.1H NMR (400 MHz, CDCl 3) 8.55 (d, J=8.0 Hz, 1H), 8.51 (d, J=8.0 Hz, 1H), 8.16 (d, J=2.0 Hz, 1H), 7.92 (d, J=8.0 Hz, 1H), 7.76 (m, 7H), 7.41 (d, J=8.4 Hz, 1H), 7.32 (d, J=8.0 Hz, 2H), 7.24 (d, J=8.0 Hz, 1H), 4.10 (m, 4H), 2.42 (s, 3H), 1.76 (m, 4H).
General procedure for the synthesis of the compound PLC-41.4- (2, 6-dichloro-4- (4- (1, 3-dioxo-9- (4- (trifluoromethyl) phenyl) -1H-xantheno [2,1,9-def ] isoquinoline-2 (3H) butoxy) benzaldehyde): A25 mL vial was charged with PLC-41.3 (131.5 mg,0.20 mmol) and 4-hydroxy-2, 6-dichlorobenzaldehyde (42.0 mg,0.22 mmol) in DMF (5 mL.) the solution was degassed at room temperature, K2CO3 (41.4 mg,0.30 mmol) was added the reaction was further degassed at room temperature, then it was warmed to 65℃and kept stirring overnight at this temperature TLC (50% EtOAc in hexanes) showed the reaction was complete, the reaction mixture was purified by flash chromatography on silica gel using EtOAc in hexanes (5% -40%) as eluent to give the pure compound PLC-41.4 as a yield solid, 27.0mg, two steps yield 20%. MS (APCI): calculated for formula C36H22Cl2F3NO5 ([ M-H ] -) =676, found 676.1H NMR (400 mhz, cdcl 3) delta 10.37 (s, 1H), 8.67 (d, j=8.0 hz, 1H), 8.63 (d, j=8.0 hz, 1H), 8.26 (d, j=2.4 hz, 1H), 8.05 (d, j=8.0 hz, 1H), 7.78 (bs, 4H), 7.75 (M, 1H), 7.49 (d, j=8.0 hz, 1H), 7.35 (d, j=8.0 hz, 1H), 6.88 (s, 2H) 4.26 (m, 2H), 4.09 (m, 2H), 1.96 (m, 4H).
Synthesis of Compound PLC-41- (2- (4- (3, 5-dichloro-4- (19, 19-difluoro-6,7,11,12,13,19-hexahydro-5H-18 l4,19l 4-benzo [3',4 ]' ]Cyclohepta [1',2':4,5]Pyrrolo [1,2-c]Benzo [3',4 ]']Cyclohepta [1',2':4,5]Pyrrolo [2,1-f][1,3,2]Diazaborane-9-yl) phenoxy) butyl) -9- (4- (trifluoromethyl) phenyl) -1H-xantho [2,1,9-def]General procedure for isoquinoline-1, 3 (2H) -dione: a 50mL 2-neck round bottom flask was fitted with an air condenser and a stir bar. To the flask were added PLC-41.4 (27.0 mg,0.04 mmol) and Ex-7.3 (15.3 mg,0.084 mmol) followed by anhydrous dichloromethane (5 ml). The reaction mixture was degassed at room temperature and then p-TsOH.H was added 2 O (0.2 mg, 0.002mmol). The reaction solution was kept at this temperature for 2 hours. DDQ (5.0 mg,0.02 mmol) was then added. The reaction was kept at room temperature for 1 hour. BF was then added at room temperature 3 ·OET 2 (59. Mu.L, 0.48 mmol) and Et 3 N (44. Mu.L, 0.32 mmol). The reaction mixture was kept at room temperature overnight. The reaction mixture was loaded with silica gel and purified by flash chromatography using EtOAc (0-3%) in DCM as eluent to give pure PLC-41 as a dark purple solid, 12.0mg,28% yield. MS (APCI): the chemical formula: C62H43BCl2F5N3O4 ([ M-H)]Calculated value of (-) = 1070, found: 1070.1H NMR (400 MHz, CDCl 2) 8.69 (d, J=8.0 Hz, 1H), 8.64 (d, J=8.0 Hz, 1H), 8.28 (d, J=2.4 Hz, 1H), 8.09 (d, J=8.0 Hz, 1H), 8.05 (m, 2H), 7.79 (m, 5H), 7.53 (d, J=8.0 Hz, 1H), 7.38 (m, 5H), 7.30 (m, 2H), 7.08 (s, 2H), 6.48 (s, 2H), 4.30 (bs, 2H), 4.14 (bs, 2H), 2.64 (m, 4H), 2.32 (m, 4H), 2.00 (m, 8H).
Synthesis of Compound PLC-42
Synthesis of Compound PLC-42.1- (9-bromo-2- (2- (2- (2-hydroxyethoxy) ethoxy) ethyl) -1H-xantho [2,1,9-def]General procedure for isoquinoline-1, 3 (2H) -dione: a100 mL flask was equipped with a stir bar. Into the flask, compound Ex-4.3 (1.3 g,3.4 mmol), 2- (2- (2-aminoethoxy) ethoxy) ethan-1-ol (1.0 g,6.8 mmol) and DMAP (29.0 mg,0.24 mmol) in DMF (25 ml) were degassed at room temperature. The reaction mixture was heated to 165 ℃ and the reaction was maintained at that temperature for 2 hours. TLC and LCMS showed the reaction was complete. The reaction was cooled to 50 ℃. Will dissolveThe solution was poured into a pre-chilled acetone (100 ml) solution with an ice-water bath. The mixture was kept at this temperature for 2 hours and then at room temperature overnight. The precipitate was collected by filtration. The solid was treated with H 2 O (150 ml) was washed and dried further in a vacuum oven at 100deg.C for 3 hours to give PLC-42.1 as a brown solid which was used in the next step without further purification. 805.0mg,48% yield. MS (APCI): the chemical formula: C24H20BrNO6 ([ M-H)]Calculated value of (-) =498, found: 498.1H NMR (400 MHz, CDCl 2) 8.61 (d, J=8.0 Hz, 1H), 8.58 (d, J=8.0 Hz, 1H), 8.18 (d, J=2.4 Hz, 1H), 7.91 (d, J=8.0 Hz, 1H), 7.64 (dd, J=8.0 Hz, J=2.4 Hz, 2H), 7.32 (d, J=8.0 Hz, 1H), 7.28 (d, J=8.0 Hz, 1H), 4.42 (t, J=6.0 Hz, 2H), 3.83 (t, J=6.0 Hz, 2H), 3.63 (m, 8H).
Synthesis of Compound PLC-42.2- (2- (2-hydroxyethoxy) ethoxy) ethyl) -9- (4- (trifluoromethyl) phenyl) -1H-xantho [2,1,9-def]General procedure for isoquinoline-1, 3 (2H) -dione: the 250mL flask was fitted with a stir bar. Into a flask, the flask was filled with THF/DMF/H 2 Compounds 1621-36 (800.0 mg,1.6 mmol), 4- (trifluoromethyl) phenylboronic acid (609.8 mg,3.2 mmol), pd (dppf) Cl in O (44 ml/8.8ml/4.4 ml) 2 (82.4 mg,0.1 mmol) and K 2 CO 3 (600.0 mg,4.4 mmol) was degassed at room temperature. The reaction mixture was heated to 80 ℃ and the reaction was maintained at that temperature overnight. TLC was used to monitor the reaction. After completion, by adding H 2 O (150 ml) was treated to precipitate the product. The precipitate was collected by filtration. The solid was treated with H 2 O (200 ml) and MeOH (20 ml) were washed and further dried in a vacuum oven at 100deg.C for 3 hours to give PLC-42.2 as a yellow solid which was used in the next step without further purification. Quantitative yield. MS (APCI): the chemical formula: C31H24F3NO6 ([ M+H)]Calculated +) 564, found: 564.1H NMR (400 MHz, CDCl 2) 8.67 (d, J=8.0 Hz, 1H), 8.61 (d, J=8.0 Hz, 1H), 8.26 (d, J=2.0 Hz, 1H), 8.07 (d, J=8.0 Hz, 1H), 7.96 (bs, 1H), 7.80 (m, 5H), 7.52 (d, J=8.4 Hz, 1H), 7.37 (d, J=8.4 Hz, 1H), 4.43 (t, J=6.0 Hz, 2H), 3.84 (t, J=6.0 Hz, 2H), 3.70 (m, 2H), 3.64 (m, 4H), 3.54 (m, 2H).
Synthesis of Compound PLC-42.3- (2- (2- (1, 3-dioxo-9-)(4- (trifluoromethyl) phenyl) -1H-xantheno [2,1,9-def]General procedure for isoquinolin-2 (3H) -yl) ethoxy) ethyl 4-methylbenzenesulfonate: a100 mL flask was equipped with a stir bar. To the flask were added compound 1621-41 (300.0 mg,0.53 mmol) and NMP (8 ml). The solution was degassed at room temperature. Para-toluenesulfonic anhydride (522.2 mg,1.6 mmol) and TEA (162.0 mg,1.6 mmol) were added. The solution was then heated to 90 ℃ and kept at that temperature overnight. TLC and LCMS were used to monitor the reaction. The reaction remained at 90 conversion even with prolonged time. After adding more p-toluenesulfonic anhydride (130.0 mg), the conversion could be increased to 97%. The reaction was cooled to room temperature. Adding H 2 O (100 ml). The mixture was extracted with DCM (150 ml x 3). The combined organic phases were taken up in anhydrous Na 2 SO 4 Dried and concentrated under vacuum rotary evaporator to give PLC-42.3 as a yellow solution (with NMP as residue) which was used in the next step without further purification. MS (APCI): the chemical formula: C38H30F3NO8S ([ M-H)]Calculated = 717, found: 717.1H NMR (400 MHz, CDCl 2) 8.64 (d, J=8.0 Hz, 1H), 8.58 (d, J=8.0 Hz, 1H), 8.26 (d, J=2.4 Hz, 1H), 8.06 (d, J=8.0 Hz, 1H), 7.76 (m, 7H), 7.51 (d, J=8.4 Hz, 1H), 7.34 (m, 3H), 4.38 (t, J=6.0 Hz, 2H), 4.05 (m, 2H), 3.76 (t, J=6.0 Hz, 2H), 3.61 (m, 4H), 3.54 (m, 2H), 2.42 (s, 3H).
Synthesis of Compound PLC-42.4- (2, 6-dichloro-4- (2- (2- (1, 3-dioxo-9- (4- (trifluoromethyl) phenyl) -1H-xantho [2,1, 9-def)]Isoquinoline-2 (3H) -yl) ethoxy) benzaldehyde). A25 mL vial was charged with PLC-42.3 (186.6 mg,0.26 mmol) and 4-hydroxy-2, 6-dichlorobenzaldehyde (54.6 mg,0.29 mmol) in DMF (5 mL). The solution was degassed at room temperature and K was added 2 CO 3 (53.8 mg,0.39 mmol). The reaction was further degassed at room temperature. It was then warmed to 65 ℃ and kept stirring at that temperature overnight. TLC (50% etoac in hexanes) showed the reaction was complete. The reaction mixture was purified by flash chromatography on silica gel using EtOAc in hexanes (0-40% -60%) as eluent to give pure compound PLC-42.4 as a yield solid, 37.0mg, 19% in two steps. MS (APCI): the chemical formula: C38H26Cl2F3NO7([M-H]Calculated = 736, found: 736.1H NMR (400 MHz, CDCl 2) δ10.20 (s, 1H), 8.62 (d, J=8.0 Hz, 1H), 8.57 (d, J=8.0 Hz, 1H), 8.20 (d, J=2.0 Hz, 1H), 8.01 (d, J=8.0 Hz, 1H), 7.80 (s, 4H), 7.76 (dd, J=8.0 Hz,2.0Hz, 1H), 7.47 (d, J=8.0 Hz, 1H), 7.33 (d, J=8.0 Hz, 1H), 6.69 (s, 2H), 4.45 (t, J=6.0 Hz, 2H), 3.86 (m, 4H), 3.72 (m, 6H).
Synthesis of Compound PLC-42- (2- (2- (2- (3, 5-dichloro-4- (19, 19-difluoro-6,7,11,12,13,19-hexahydro-5H-18 l4,19l 4-benzo [3',4 ') ] ']Cyclohepta [1',2':4,5]Pyrrolo [1,2-c]Benzo [3',4 ]']Cyclohepta [1',2':4,5]Pyrrolo [2,1-f][1,3,2]Diazaborane-9-yl) phenoxy) ethoxy) ethyl) -9- (4- (trifluoromethyl) phenyl) -1H-xantho [2,1,9-def]General procedure for isoquinoline-1, 3 (2H) -dione: a 100mL 2-neck round bottom flask was fitted with an air condenser and a stirrer bar. To the flask were added PLC-42.4 (37.0 mg,0.05 mmol) and 1605-44 (19.3 mg,0.11 mmol) followed by anhydrous dichloromethane (5 ml). The reaction mixture was degassed at room temperature and then p-TsOH.H was added 2 O (0.3 mg, 0.003mmol). The reaction solution was kept at this temperature for 2 hours. DDQ (6.2 mg,0.03 mmol) was then added. The reaction was kept at room temperature for 1 hour. BF was then added at room temperature 3 ·OEt 2 (74. Mu.L, 0.6 mmol) and Et 3 N (56. Mu.L, 0.4 mmol). The reaction mixture was kept at room temperature overnight. The reaction mixture was loaded with silica gel and purified by flash chromatography using EtOAc (0-6%) in DCM as eluent to give pure PLC-42 as a dark purple solid, 7.0mg,13% yield. MS (APCI): the chemical formula: C64H47BCl2F5N3O6 ([ M-H) ]Calculated = 1130, found: 1130.1H NMR (400 MHz, CDCl 2) 8.68 (d, J=8.0 Hz, 1H), 8.63 (d, J=8.0 Hz, 1H), 8.26 (d, J=2.4 Hz, 1H), 8.08 (d, J=8.0 Hz, 1H), 8.04 (m, 2H), 7.78 (bs, 4H), 7.78 (dd, J=8.0 Hz,2.0Hz, 1H), 7.50 (d, J=8.0 Hz, 1H), 7.37 (m, 5H), 7.29 (m, 2H), 7.07 (s, 2H), 6.46 (s, 2H), 4.46 (t, J=8.4 Hz, 2H), 4.13 (t, J=4.4 Hz, 2H), 3.86 (m, 4H), 3.74 (m, 4H), 2.63 (m, 4H), 2.31 (bs, 2.04).
Synthesis of Compound PLC-43
Synthesis of the Compound PLC-43.1- (2- (3-hydroxypropyl) -9- (perfluorophenyl) -1H-xantheno [2,1,9-def]General procedure for isoquinoline-1, 3 (2H) -dione: a100 mL flask was equipped with a stir bar. Into a flask, compound PLC-38.1 (400.0 mg,0.9 mmol), (perfluorophenyl) boronic acid (240.0 mg,1.1 mmol), pd in DMF (30 ml) 2 (dba) 3 (43.0mg，0.05mmol)、CsF(285.6mg，1.9mmol)、Ag 2 O (259.4 mg,1.1 mmol) and (t-Bu) 3 P (1.9 ml,1.9 mmol) was degassed at room temperature. The reaction mixture was heated to 80 ℃ and the reaction was maintained at that temperature overnight. TLC was used to monitor the reaction. After completion, the reaction was purified by flash chromatography on silica gel using EtOAc in hexanes (5-10-50-70%) as eluent to give pure compound PLC-43.1 as a yellow solid in 136.0mg,28% yield. MS (APCI): the chemical formula: C27H14F5NO4 ([ M-H) ]Calculated = 511, found: 511.1H NMR (400 MHz, CDCl 2) 8.57 (d, J=8.0 Hz, 1H), 8.55 (d, J=8.0 Hz, 1H), 8.07 (s, 1H), 7.92 (d, J=8.0 Hz, 1H), 7.53 (d, J=8.0 Hz, 1H), 7.46 (d, J=8.0 Hz, 1H), 7.32 (d, J=8.0 Hz, 1H), 4.25 (t, J=6.0 Hz, 2H), 3.48 (m, 2H), 3.07 (t, J=6.8 Hz, 1H), 1.90 (m, 2H).
Synthesis of the Compound PLC-43.2- (2- (3-bromopropyl) -9- (perfluorophenyl) -1H-xantho [2,1,9-def]General procedure for isoquinoline-1, 3 (2H) -dione: a100 mL flask was equipped with a stir bar. To the flask was added compound 1644-10 (136.0 mg,0.3 mmol), CBr 4 (176.3mg，0.5mmol)、PPh 3 (140.2 mg,0.5 mmol) and DCE (12 ml). The solution was degassed at room temperature. The reaction was held at this temperature for 30 minutes. TLC and LCMS were used to monitor the reaction. After completion, the reaction was purified by flash chromatography on silica gel using EtOAc in hexanes (5-10-50-70%) as eluent to give pure compound PLC-43.2 as a yellow solid, 116.0mg,76% yield. MS (APCI): the chemical formula: C27H13BrF5NO3 ([ M+H)]Calculated +) = 573, found: 573.1H NMR (400 MHz, CDCl 2) 8.64 (d, J=8.0 Hz, 1H), 8.61 (d, J=8.0 Hz, 1H), 8.15 (d, J=1.6 Hz, 1H), 7.99 (d, J=8.0 Hz, 1H), 7.61 (m, 1H), 7.54 (d, J=8.0 Hz, 1H), 7.39 (d, J=8.0 Hz, 1H), 4.32 (t, J=6.8 Hz, 2H), 3.54 (t ,J＝6.8Hz,2H),2.34(quintet,J＝6.8Hz,2H)。
Synthesis of Compound PLC-43- (2- (3, 5-dichloro-4- (19, 19-difluoro-6,7,11,12,13,19-hexahydro-5H-18 l4,19l 4-benzo [3',4 ') ']Cyclohepta [1',2':4,5]Pyrrolo [1,2-c]Benzo [3',4 ]']Cyclohepta [1',2':4,5]Pyrrolo [2,1-f][1,3,2]Diazaborane-9-yl) phenoxy) propyl) -9- (perfluorophenyl) -1H-xantheno [2,1,9-def]General procedure for isoquinoline-1, 3 (2H) -dione: to a 25ml vial, PLC-1.3 (73.4 mg,0.1 mmol), PLC-43.2 (60.0 mg,0.1 mmol), K were added 2 CO 3 (28.7 mg,0.2 mmol) and DMF (2 ml). The mixture was sonicated for 2 minutes at room temperature. It was then warmed to 75 ℃ and kept stirring at that temperature for 4 hours. TLC (50% etoac in hexanes) showed the reaction was complete. The reaction mixture was purified by flash chromatography on silica gel using EtOAc (0-3%) in DCM as eluent to give pure compound PLC-43 as a dark purple solid, 91.0mg,81% yield. MS (APCI): the chemical formula: C60H37BCl2F7N3O4 ([ M-H)]Calculated = 1077, found: 1077.1H NMR (400 MHz, CDCl 2) 8.67 (d, J=8.0 Hz, 1H), 8.63 (d, J=8.0 Hz, 1H), 8.18 (bs, 1H), 8.05 (m, 2H), 8.01 (d, J=8.0 Hz, 1H), 7.61 (m, 1H), 7.54 (d, J=8.0 Hz, 1H), 7.38 (m, 5H), 7.30 (m, 2H), 7.02 (s, 2H), 6.47 (s, 2H), 4.44 (t, J=6.0 Hz, 2H), 4.22 (t, J=6.0 Hz, 2H), 2.64 (m, 4H), 2.32 (m, 6H), 2.05 (m, 4H).
Synthesis of Compound PLC-44
Compound PLC-44.1:9- (3, 5-bis (trifluoromethyl) phenyl) -2- (3-hydroxypropyl) -1H-xantheno [2,1,9-def]Isoquinoline-1, 3 (2H) -dione: compound PLC-38.1 (0.4241 g,1.0mmol,1 eq) was suspended in DMF (5 ml), H 2 To O (0.5 ml), added were (bis-3, 5-trifluoromethyl) phenylboronic acid (0.51586 g,2.0mmol,2 eq) and K 2 CO 3 (0.27642g，2.0mmol，2eq)、Pd(dppf)Cl 2 DCM (16.33 mg,0.02mmol,0.02 eq). The resulting mixture Vac-Fill Argon was cycled 3 times, stirred and heated at 80℃for 45 minutes, the mixture became viscous, 15ml of DMF was added and stirring was continued at 80℃For an additional 15 minutes. The reaction mixture was cooled to room temperature, concentrated by rotary evaporator, water was added to the residual mixture, and kept at room temperature for 1 hour. The precipitate was filtered to give 570mg of a greenish-yellow solid which was washed with MeOH to give 270mg of pure product. The yield was 48%. MS (APCI): the chemical formula: calculated for C29H17F6NO4 (M-) =557; actual measurement value: 557.1H NMR (400 MHz,) δ8.60 (d, j=7.9 hz, 1H), 8.55 (d, j=8.4 hz, 1H), 8.17 (d, j=2.2 hz, 1H), 8.03 (d, j=8.1 hz, 1H), 8.00 (s, 2H), 7.87 (s, 1H), 7.70 (dd, j=8.7, 2.1hz, 1H), 7.47 (d, j=8.6 hz, 1H), 7.31 (d, j=8.3 hz, 1H), 4.25 (t, j=6.2 hz, 2H), 3.49 (d, j=6.1 hz, 3H), 3.08 (t, j=6.8 hz, 1H), 1.90 (t, j=6.0 hz, 2H).
Compound PLC-44.2:9- (3, 5-bis (trifluoromethyl) phenyl) -2- (3-bromopropyl) -1H-xantho [2,1,9-def ] isoquinoline-1, 3 (2H) -dione: a mixture of PLC-44.1 (5538 mg,1.0 mmol) in 48% aqueous HBr (30.0 ml) was heated to reflux via a heated block at 130℃for 16 hours. LCMS showed >90% conversion. After cooling to room temperature, the solid was filtered, washed with water and dried in a vacuum oven to give the desired compound with some unreacted SM. 600mg of a green-yellow solid was obtained in 86% yield. The product was used in the next step without further purification. MS (APCI): the chemical formula: calculated for C29H16BrF6NO34 (M-) =620; actual measurement value: 620.1H NMR (400 MHz) delta 8.58 (d, J=7.8 Hz, 1H), 8.53 (d, J=8.4 Hz, 1H), 8.16 (d, J=2.3 Hz, 1H), 8.04-7.97 (m, 2H), 7.86 (s, 1H), 7.70 (dd, J=8.6, 2.2Hz, 1H), 7.46 (d, J=8.6 Hz, 1H), 7.30 (d, J=8.3 Hz, 1H), 4.23 (t, J=7.1 Hz, 2H), 3.45 (t, J=6.8 Hz, 2H), 2.34-2.16 (m, 2H).
Compound PLC-44:9- (3, 5-bis (trifluoromethyl) phenyl) -2- (3, 5-dichloro-4- (19, 19-difluoro-6,7,11,12,13,19-hexahydro-5H-18 l4,19l 4-benzo [3',4 ]']Cyclohepta [1',2':4,5]Pyrrolo [1,2-c]Benzo [3',4 ]']Cyclohepta [1',2':4,5]Pyrrolo [2,1-f][1,3,2]Diazaborane-9-yl) phenoxy) propyl) -1H-xantheno [2,1,9-def ]Isoquinoline-1, 3 (2H) -dione: compound PLC-44.2 (46.52 mg,0.075mmol,1.15 eq) was suspended in anhydrous DMF (2.0 ml), and PLC-1.3 (38.04 mg,0.065mmol,1 eq), K was added 2 CO 3 (20.73 mg,0.15mmol,2.3 eq), naI (4.15 mg, catalytic amount). The resultant was stirred at 85℃under an argon atmosphereMix for 3 hours. The mixture was filtered, the solid was washed with 50ml of water, then loaded onto a 40g column, eluted with Hex: DCM (9:1 to DCM only), and the product from the column was washed with EtOH to give 53mg of a dark purple solid. The yield was 62%. MS (APCI): the chemical formula: calculated for C62H40BCl2F8N3O4 (M-) =1124; actual measurement value: 1124.1H NMR (400 MHz) delta 8.61 (d, J=7.8 Hz, 1H), 8.55 (d, J=8.3 Hz, 1H), 8.16 (d, J=2.2 Hz, 1H), 8.04 (d, J=8.1 Hz, 1H), 8.00 (s, 2H), 7.95 (t, J=4.7 Hz, 2H), 7.86 (s, 1H), 7.70 (dd, J=8.6, 2.2Hz, 1H), 7.47 (d, J=8.6 Hz, 1H), 7.32 (d, J=8.3 Hz, 1H), 7.27 (dt, J=7.4, 3.7Hz, 3H), 7.23-7.15 (m, 2H), 6.92 (s, 2H), 6.38 (s, 2H), 4.36 (t, J=7.0 Hz, 2H), 4.13 (t, 6.6 Hz, 1H), 7.32 (d, J=8.3 Hz, 1H), 7.27 (dt, J=7.4 Hz, 3.7H), 6.23-7.15 (m, 2H), 6.92 (t, 2H).
Synthesis of Compound PLC-45:
compound PLC-45.1:4'- (tert-butyl) -3-nitro- [1,1' -biphenyl]-4-alcohol: 4-bromo-2-nitro-phenol (5.45 g,25.0 mmol) and 4- (tert-butyl) phenylboronic acid (5.563 g,31.25 mmol) were dissolved in dioxane (100 mL) at room temperature and stirred for 5 min. After forming the clear solution, pd (PPh 3 ) 2 cl 2 (0.175 g,0.25 mmol), and K of 4N 2 CO 3 Aqueous (25.0 ml,50mmol,2 eq); the mixture was degassed by 3 cycles of Vac-Fil Nitrogen and then heated at 80℃for 4 hours. After cooling the reaction to room temperature, the pH was adjusted to 5-6 with 4N aqueous HCl, extracted with ethyl acetate (250 mL) and passed through a short pad of celite. The pad was washed with EA (150 ml. Times.2). The organic layers were combined and washed with brine (25 mL), over anhydrous MgSO 4 Dried, and concentrated under reduced pressure. The residue was dissolved in Hex:EA (95:5) (150 ml), the dark solid was filtered off through a short celite pad, and the filtrate was concentrated to give a yellow solid which was triturated with hexane to give 3.8 as a yellow solid in 56% yield. MS (APCI): the chemical formula: calculated value of C16H17NO3 (M-) =271; actual measurement value: 271.1H NMR (400 MHz, chloroform-d) δ10.57 (s, 1H), 8.32 (d, J=2.3 Hz, 1H), 7.83 (dd, J=8.7, 2.4Hz, 1H), 7.50 (d, J=1.5)Hz,4H),7.23(d,J＝8.7Hz,1H),1.37(s,9H)。
Compound PLC-45.2: 4-bromonaphthalene dicarboxylic anhydride (10 g,36mmol,1.15 eq), 4'- (tert-butyl) -3-nitro- [1,1' -biphenyl ] -4-ol (PLC-45.1) (8.5 g,31.32mmol,1 eq), naOH (0.864 g,21.6mmol,0.6 eq) were mixed in anhydrous NMP (65 mL) and copper powder (1.371 g,21.6mmol,0.6 eq) was added. The resulting mixture was degassed by 3 cycles of Vac-Fil Nitrogen, then heated and stirred at 145 ℃ under an N2 atmosphere for 5 hours, then room temperature overnight. Treating the reaction mixture with aqueous HCl; after 12 hours of standing at room temperature, the brown solid was precipitated, filtered, and washed with hot MeOH (250 ml. Times.3) to give (10.8 g,23.1 mmol) a pale brown solid, 73% yield, 86% purity. MS (APCI): the chemical formula: calculated for C28H21NO6 (M-) =467; actual measurement value: 467.
Compound PLC-45.3:6- ((3-amino-4 '- (tert-butyl) - [1,1' -biphenyl)]-4-yl) oxy) -1H, 3H-benzo [ de ]]Isochromene-1, 3-dione: to a mixture of PLC-45.2 (4.885 g,10.45mmol,1.0 eq) in 2-MeTHF (70.0 mL) and HCl (4M, 26.1mL,10 eq) was added SnCl in one portion 2 .2H 2 O (9.4 g,41.75mmol,4.0 eq). The mixture was stirred at 90℃for 1/2 hour. TLC (hexane/ethyl acetate=7:3) and LCMS showed the reaction was complete. The white solid was filtered off and washed with EA/2-MeTHF (1:1) (100 mL. Times.2). The combined organic filtrates were washed with water, separated and concentrated under reduced pressure to give a viscous solid residue. The crude product was washed with 100mL hot water at 50deg.C for 1/2 h, filtered, and then dried under reduced pressure to give PLC-45.3 (4.5 g,10.28 mmol) as a yellowish-brown solid. Yield 98%. MS (APCI): the chemical formula: calculated for C28H23NO4 (M-) =437; actual measurement value: 437.
compound PLC-45.4:9- (4- (tert-butyl) phenyl) -1H, 3H-isochromeno [6,5,4-mna]Xanthene-1, 3-dione: at 0deg.C, to a reaction mixture of AcOH (28.5 mL) and H 2 Compound PLC-45.3 (1.844 g,4.215mmol,1.0 eq) in O (9.0 mL) was added dropwise concentrated HCl (2.445 mL) and under H 2 NaNO in O (9 mL) 2 (2.9 g,42.15mmol,10 eq) and stirred at 0℃for 1 hour. The above solution was added to the solution at H through a dropping funnel at 130℃over a period of 1/2 hour 2 CuS in O (175 ml), acOH (11 ml)O 4 ·5H 2 O (4.35 g,17.42mmol,4.1 eq). After the addition was complete, the resulting mixture was stirred at 130℃for a further 15 minutes at the same temperature. The mixture was filtered and treated with H 2 O (3X 100 mL) gave 0.445g of crude product which was triturated with EtOH to give 0.42g of pure compound in 30% yield. MS (APCI): the chemical formula: calculated for C28H20O4 (M-) =420; actual measurement value: 420.
compound PLC-45.5:9- (4- (tert-butyl) phenyl) -2- (3-hydroxypropyl) -1H-xantho [2,1,9-def ] isoquinoline-1, 3 (2H) -dione: to compound PLC-45.4 (0.420 g,1.0mmol,1.0 eq) in anhydrous DMSO (4 mL) was added 3-amino-1-propanol (0.300 g,4.0mmol,4.0 eq) and the resulting mixture was stirred at 130℃for 45 min. After the reaction was completed, DMSO was removed by filtration. The solid was washed with water (50 ml×3) and dried in a vacuum oven to give 0.45g yellow solid; the yield was 94%. MS (APCI): the chemical formula: calculated for C31H27NO4 (M-) =477; actual measurement value: 477.1H NMR (400 MHz, chloroform-d) δ10.44 (s, 2H), 8.65 (d, J=7.8 Hz, 1H), 8.60 (d, J=8.3 Hz, 1H), 8.25 (d, J=2.0 Hz, 1H), 8.03 (d, J=8.0 Hz, 1H), 7.76 (dd, J=8.6, 2.1Hz, 1H), 7.61 (d, J=8.3 Hz, 2H), 7.54 (d, J=8.2 Hz, 2H), 7.45 (d, J=8.6 Hz, 1H), 7.32 (d, J=8.3 Hz, 1H), 6.50 (s, 2H), 4.42 (t, J=6.9 Hz, 2H), 4.17 (t, J=6.2 Hz, 2H), 2.54 (s, 6H), 2.28 (s, 2H), 1.40 (s, 9H).
Compound PLC-45.6:2- (3-bromopropyl) -9- (4- (tert-butyl) phenyl) -1H-xantho [2,1,9-def ] isoquinoline-1, 3 (2H) -dione: a mixture of 1643-002 (0.457 g,0.95 mmol) and 48% aqueous HBr (20 ml) was stirred and heated by a heated block at 130℃for 8 hours. LCMS showed SM was fully depleted. The mixture was cooled to room temperature and left to stand at room temperature for 16 hours. The yellow solid was filtered, washed several times with water and dried in a vacuum oven to give 0.275g in 96% yield. The product was used in the next step without further purification. MS (APCI): the chemical formula: calculated for C31H26BrNO3 (M-) =540; actual measurement value: 540.1H NMR (400 MHz) delta 8.59 (d, J=7.8 Hz, 1H), 8.53 (d, J=8.4 Hz, 1H), 8.19 (s, 1H), 7.99 (d, J=8.0 Hz, 1H), 7.72 (d, J=8.7 Hz, 1H), 7.55 (d, J=8.0 Hz, 2H), 7.45 (d, J=8.0 Hz, 2H), 7.41 (d, J=8.5 Hz, 1H), 7.29 (d, J=8.4 Hz, 1H), 4.25 (s, 2H), 3.48 (d, J=6.1 Hz, 2H), 3.16 (d, J=6.8 Hz, 1H), 1.90 (s, 2H), 1.31 (s, 9H).
Compound PLC-45:9- (4- (tert-butyl) phenyl) -2- (3, 5-dichloro-4- (19, 19-difluoro-6,7,11,12,13,19-hexahydro-5H-18 l4,19l 4-benzo [3',4 ]']Cyclohepta [1',2':4,5]Pyrrolo [1,2-c]Benzo [3',4 ]']Cyclohepta [1',2':4,5]Pyrrolo [2,1-f][1,3,2]Diazaborane-9-yl) phenoxy) propyl) -1H-xantheno [2,1,9-def ]Isoquinoline-1, 3 (2H) -dione: compound PLC-45.6 (40.53 mg,0.075mmol,1.15 eq) was suspended in anhydrous DMF (2.0 ml) and PLC-1.3 (38.04 mg,0.065mmol,1 eq), K was added 2 CO 3 (20.73 mg,0.15mmol,2.3 eq), naI (4.15 mg, catalytic amount). The resulting mixture was stirred at 85 ℃ under an argon atmosphere for 4 hours. DMF and water were removed by rotary evaporator at 53 ℃; the residue was washed with 50ml of hot water and then loaded onto a 40g column, eluting with Hex: DCM (9:1 to DCM (4 CV) only, then DCM/EtAcO (99:1), the product purified from column chromatography was washed with hot water to give 27mg of a dark purple solid, yield 38.5%. MS (APCI), calculated for C64H50BCl2F2N3O4 (M-) = 1044; found: 1044.1H NMR (400 MHz, chloroform-d) delta 8.70 (d, J = 7.9hz, 1H), 8.64 (d, J = 8.4hz, 1H), 8.25 (d, J = 2.2hz, 1H), 8.09 (d, J = 7.3hz, 2H), 8.05 (d, J = 8.0hz, 1H), 7.76 (dd, J = 8.6,2.1hz, 1H), 7.60 (d, J = 8.9 hz), 7.4 hz (d, 7.4 hz), 7.7.7.7 (d, 4 hz), 7.7.7H), 7.25 (d, J = 2.2hz, 1H), 8.7.7.7 (d, 7H), 7.7.7H), 7.7 (d = 7.7 hz, 1H), 7.7.7.7H (d, 7H), 7.7.7H (d, 7H), 7.7.7H (d, 1H), 7.7.7.7H), 7.05 (d, 7.7.7H).
Synthesis of Compound PLC-46:
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compound PLC-46.2:9- (3, 5-bis (trifluoromethyl) phenyl) -2- (2-hydroxyethyl) -1H-xantheno [2,1,9-def]Isoquinoline-1, 3 (2H) -dione: step 1: a mixture of Ex-4.3 (0.730 g,2.0mmol,1.0 eq) and 3-amino-1-ethanol (0.732 g,12.0mmol,6.0 eq) was placed in a 20mL vial and sealed with a septum cap. The resulting mixture was stirred at 160℃for 45 minutes. After cooling toAfter room temperature, the reaction was stirred with MeOH (10 mL) at room temperature for 15 minutes, then filtered. The crude PLC-46.1 was used in the next step without further purification. MS (APCI): the chemical formula: calculated for C20H12BrNO4 (M-) =410; actual measurement value: 410.1H NMR (400 MHz, chloroform-d) δ8.62 (d, J=8.3 Hz, 1H), 8.20 (d, J=2.3 Hz, 1H), 7.93 (d, J=7.9 Hz, 1H), 7.62 (dd, J=8.8, 2.3Hz, 1H), 7.32 (d, J=8.3 Hz, 1H), 7.28 (s, 1H), 4.55-4.40 (m, 2H), 3.99 (s, 2H), 2.49 (s, 1H), 2.22 (t, J=7.6 Hz, 1H). Step 2: the crude product of the above step was taken up in DMF (5 ml), H at room temperature 2 O (0.5 ml), (bis-3, 5 trifluoromethyl) phenylboronic acid (1.031 g,4.0mmol,2 eq), K 2 CO 3 (0.553g，4.0mmol，2eq)、Pd(dppf)Cl 2 DCM (32.66 mg,0.04mmol,0.02 eq) was mixed, vac-Fill Argon was cycled 3 times, stirred and heated at 80℃for 45 minutes, the mixture became viscous, 5ml DMF was added and stirring was continued for another 15 minutes at 80 ℃. The reaction mixture was cooled to room temperature, concentrated by rotary evaporator, water was added to the residual mixture, kept at room temperature for 1 hour, and the precipitate was filtered to give 1.1g of a greenish-yellow solid, which was washed with MeOH to give 0.85g of the desired product, PLC-46.2. The yield was 80%. MS (APCI): the chemical formula: calculated value of C28H15F6NO4 (M-) =543; actual measurement 543.1H NMR (400 MHz, chloroform-d) δ8.71 (d, J=7.7 Hz, 1H), 8.65 (d, J=8.2 Hz, 1H), 8.26 (s, 1H), 8.11 (s, 1H), 8.09 (s, 1H), 8.03 (s, 3H), 7.99 (s, 1H), 7.94 (s, 1H), 7.77 (d, J=8.7 Hz, 1H), 7.53 (d, J=8.8 Hz, 2H), 7.37 (d, J=8.4 Hz, 1H), 4.49 (d, J=5.5 Hz, 2H), 4.01 (d, J=5.4 Hz, 2H), 3.73 (s, 1H).
Compound PLC-46:9- (3, 5-bis (trifluoromethyl) phenyl) -2- (2- (3, 5-dichloro-4- (19, 19-difluoro-6,7,11,12,12,19-hexahydro-5H-18 l4,19l 4-benzo [3',4 ]']Cyclohepta [1',2':4,5]Pyrrolo [1,2-c]Benzo [3',4 ]']Cyclohepta [1',2':4,5]Pyrrolo [2,1-f][1,3,2]Diazaborane-9-yl) phenoxy) ethyl) -1H-xantheno [2,1,9-def]Isoquinoline-1, 3 (2H) -dione: triphenylphosphine (39.34 mg,0.15 mmol), PLC-1.3 (76.08 g,0.13 mmol) and PLC-46.2 (81.51 g,0.15 mmol) were dissolved in anhydrous toluene (2 mL); 0.15mL of a solution of 1M DIAD/toluene+1 mL of anhydrous toluene was added dropwise over 15 minutes at room temperature. The resulting mixture was stirred under argon atmosphere for 16h. Additional triphenylphosphine (19.73 mg, 0.075) was added continuouslymmol) and 0.075mL of 1M DIAD/toluene +0.5mL of anhydrous toluene, and the mixture is stirred for a further 8 hours. Purifying: RX mixture was loaded onto 80g SiO 2 On the column, the fractions containing the desired compound were collected and concentrated by eluting with Hex: DCM (7:3), (1:4) and then DCM alone. The dark purple solid was washed with water, then MeOH, and dried in a vacuum oven to give 43mg of a dark brown purple solid; the yield was 42%. MS (APCI): the chemical formula: calculated for C61H38BCl2F8N3O4 (M-) =1110, found 1110.1H NMR (400 MHz, chloroform-d) delta 8.74 (d, J=7.9 Hz, 1H), 8.68 (d, J=8.3 Hz, 1H), 8.26 (d, J=2.2 Hz, 1H), 8.11 (d, J=8.0 Hz, 1H), 8.09-8.03 (m, 4H), 7.95 (s, 1H), 7.77 (dd, J=8.6, 2.2Hz, 1H), 7.53 (d, J=8.6 Hz, 1H), 7.38 (d, J=8.3 Hz, 1H), 7.35-7.26 (m, 4H), 7.21 (dd, J=6.8, 2.0Hz, 2H), 7.11 (s, 2H), 6.39 (s, 2H), 4.72 (t, J=6.2 Hz, 2H), 4.43 (t, J=6.6, 2Hz, 1H), 7.35-7.26 (m, 4H), 7.21 (dd, J=6.8 Hz, 2.0Hz, 2H), 4.43 (t=6.2H), 4.61 (t=6.4 Hz, 4H).
Synthesis of Compound PLC-47:
compound PLC-47.1: (9-bromo-2- (6-hydroxyhexyl) -1H-xantheno [2,1,9-def ] isoquinoline-1, 3 (2H) -dione): the compound Ex-4.3 (6.284 mmol,2.401 g), 6-aminohex-1-ol (13.08 mmol,1533 mg) and DMAP (1.962mmol, 240 mg) were combined with DMF. The crude product was filtered off and washed with water, and the wet precipitate was used in the next step without further purification. MS (APCI): the chemical formula: calculated for C24H20BrNO4 (m+h) =466; actual measurement value: 466.
compound PLC-47.2: (2- (6-hydroxyhexyl) -9- (4- (trifluoromethyl) phenyl) -1H-xantho [2,1,9-def]Isoquinoline-1, 3 (2H) -dione): will be described as THF (120 mL)/DMF (24 mL)/H 2 Compound PLC-47.1 in O (12 mL) (assuming 100% yield, 6.284 mmol,3.047 g), (4- (trifluoromethyl) phenyl) boronic acid (13.068 mmol, 2.4812 g), K 2 CO 3 (17.969 mmol,2483 mg) and Pd (dppf) Cl 2 (0.45774 mmol,335 mg) are combined at 80℃in a similar manner to the method described above. After adding water and filtering, the resulting precipitate was washed with water and then with nailWashing with alcohol. The product was dried by suction and then dried in vacuo. 1.191g (34% yield, 29.3,2 steps based on compound) are obtained. MS (APCI): the chemical formula: calculated value of C31H24F3NO4 (m+h) =532; actual measurement value: 532.
Compound PLC-47.3: (2- (6-bromohexyl) -9- (4- (trifluoromethyl) phenyl) -1H-xantho [2,1,9-def]Isoquinoline-1, 3 (2H) -dione): 250mL of 2N RBF was loaded into a stir bar and equipped with a gas connector/fin condenser and flow controller. To the flask was added compound PLC-47.2 (2.239 mmol,1.190 g) followed by 48% HBr/H 2 O (30 mL). The heating block was set to 130 ℃, and the reaction mixture was stirred at this temperature for 3 hours. Adding another portion of 48% HBr/H 2 O (30 mL) and the reaction mixture was stirred overnight at 130 ℃. The reaction mixture was cooled to room temperature and diluted with water (-100 mL), then the precipitate was filtered off, washed with water and then with methanol. The product was loaded onto-25 g of silica gel in a loader. Purification by flash chromatography on silica gel (120 g, solid loading, equilibrated 0% etoac/DCM,0% (2 CV) to 10% etoac/DCM (20 CV)). Fractions with product were collected and evaporated to dryness in vacuo. A material of about 80% purity was obtained. A yellow solid, 1.073g (80% yield) was obtained. MS (APCI): the chemical formula: calculated for C31H23BrF3NO3 (m+h) =594; actual measurement value: 594.1H NMR (400 MHz, TCE) δ8.63 (d, J=7.9 Hz, 1H), 8.58 (d, J=8.3 Hz, 1H), 8.23 (d, J=2.1 Hz, 1H), 8.03 (d, J=8.0 Hz, 1H), 7.84-7.73 (m, 5H), 7.49 (d, J=8.6 Hz, 1H), 7.34 (d, J=8.3 Hz, 1H), 4.19-4.09 (m, 2H), 3.44 (td, J=6.8, 1.9Hz, 2H), 1.90 (p, J=6.9 Hz, 2H), 1.75 (p, J=7.8 Hz, 2H), 1.57-1.38 (m, 4H).
Compound PLC-47.4: (2, 6-dichloro-4- ((6- (1, 3-dioxo-9- (4- (trifluoromethyl) phenyl) -1H-xantho [2,1, 9-def)]Isoquinolin-2 (3H) -yl) hexyl) oxy) benzaldehyde): compound PLC-47.4 in a similar manner to Compound 34.4, from Compound PLC-47.3 (0.200 mmol,119 mg), 2, 6-dichloro-4-hydroxybenzaldehyde (0.300 mmol,57 mg) and K 2 CO 3 (0.260 mmol,36 mg) in anhydrous DMF (10 mL). The crude compound was dissolved in DCM and loaded onto-5 g silica gel in a cartridge. Purification by flash chromatography on silica gel (80 g, solid loading, flat70% DCM/hexane was equilibrated, eluting 70% (2 CV) to 100% DCM/hexane (5 CV)Isocratic 100% DCM/hexane (5 CV) to 0% EtOAc/DCM (0 CV) to isocratic 0% EtOAc/DCM (5 CV)/(5 CV)>10% EtOAc/DCM (20 CV)). The product-containing fractions were evaporated to dryness in vacuo. A yellow solid, 113mg, (60% yield) was obtained. MS (APCI): the chemical formula: calculated for C38H26Cl2F3NO5 (m+h) =704; actual measurement value: 704.1H NMR (400 MHz, TCE) H10.37 (s, 1H), 8.64 (d, J=7.9 Hz, 1H), 8.59 (d, J=8.4 Hz, 1H), 8.25 (d, J=2.2 Hz, 1H), 8.05 (d, J=8.0 Hz, 1H), 7.78 (dd, J=11.2, 1.9Hz, 5H), 7.50 (d, J=8.6 Hz, 1H), 7.36 (d, J=8.3 Hz, 1H), 6.92 (s, 2H), 4.23-4.11 (m, 2H), 4.02 (t, J=6.4 Hz, 2H), 1.89-1.70 (m, 4H), 1.59-1.45 (m, 4H).
Compound PLC-47: (2- (6- (3, 5-dichloro-4- (19, 19-difluoro-6,7,11,12,13,19-hexahydro-5H-18 l4,19l 4-benzo [3',4 ') ] ']Cyclohepta [1',2':4,5]Pyrrolo [1,2-c]Benzo [3',4 ]']Cyclohepta [1',2':4,5]Pyrrolo [2,1-f][1,3,2]Diazaborane-9-yl) phenoxy) hexyl) -9- (4- (trifluoromethyl) phenyl) -1H-xantho [2,1,9-def]Isoquinoline-1, 3 (2H) -dione): compound PLC-47 in a similar manner to the above procedure, the compound PLC-47.4 (0.1164 mmol,82 mg), 1,4,5, 6-tetrahydrobenzo [6,7 ]]Cyclohepta [1,2-b ]]Pyrrole (0.2444 mmol,45mg (Ex-7.3) and pTsOH.H) 2 O (0.0058 mmol,1.1 mg), then DDQ (0.1989 mmol,45 mg) and 2 XEt 3 N (0.9312 mmol,0.130 mL) and BF 3 .OEt 2 (1.397 mmol,0.172 mL) was synthesized in anhydrous DCM (20 mL) at room temperature and then at 50deg.C. The crude reaction mixture was diluted with-25% hexane and then loaded onto-15 g silica gel in a loader. Purification by flash chromatography on silica gel (80 g, solid loading, equilibration of 70% dcm/hexane, elution of 70% (2 CV) to 100% dcm/hexane (5 CV), isocratic 100% dcm/hexane (5 CV) to 100% dcm/hexane (isocratic) 0.5% etoac modifier). The product-containing fractions were evaporated to dryness in vacuo. A dark red solid, 79mg (62% yield) was obtained. MS (APCI): the chemical formula: C64H47BCl2F5N3O Calculated value of 4 (m+h) =1098; actual measurement value: 1098.1H NMR (400 MHz, TCE) delta 8.66 (d, J=7.9 Hz, 1H), 8.61 (d, J=8.3 Hz, 1H), 8.26 (d, J=2.1 Hz, 1H), 8.10-8.01 (m, 3H), 7.78 (dd, J=9.4, 1.7Hz, 5H), 7.55-7.46 (m, 5H), 7.43-7.32 (m, 5H), 7.33-7.25 (m, 2H), 7.07 (s, 2H), 6.48 (s, 2H), 4.20 (t, J=7.7 Hz, 2H), 4.06 (t, J=6.3 Hz, 2H), 2.63 (t, J=6.9 Hz, 4H), 2.42-2.19 (m, 4H), 2.08-2.00 (m, 2H), 1.88 (q, J=7.07 (s, 2H), 6.48 (s, 2H), 4.20 (t, J=6.7 Hz, 2H), 1.42-2.19 (m, 1.3H).
Synthesis of Compound PLC-48
Compound PLC-48.2 (4- (2- (3, 5-dichloro-4-formylphenoxy) propyl) -1, 3-dioxo-2, 3-dihydro-1H-xantho [2,1, 9-def)]Isoquinolin-9-yl) benzoic acid tert-butyl ester): compound PLC-48.2 in a similar manner to the procedure described above, the reaction mixture was prepared from compound PLC-48.1 (0.1471 mmol), 2, 6-dichloro-4-hydroxybenzaldehyde (0.441 mmol,84 mg) and K 2 CO 3 (0.4120 mmol,57 mg) was synthesized in anhydrous DMF (10 mL). The crude reaction was diluted with crushed ice (-50 g). Once it is totally melted, the crude product is separated by centrifugation. The product was dissolved in DCM and evaporated to dryness in vacuo. A yellow solid was obtained in quantitative yield. MS (APCI): the chemical formula: calculated for C39H29Cl2NO7 (m+h) =694; actual measurement value: 694.1H NMR (400 mhz, tce) δ10.37 (s, 1H), 8.64 (d, j=7.9 hz, 1H), 8.59 (d, j=8.3 hz, 1H), 8.28 (d, j=2.2 hz, 1H), 8.13 (d, j=8.1 hz, 2H), 8.07 (d, j=8.0 hz, 1H), 7.81 (dd, j=8.6, 2.1hz, 1H), 7.75 (d, j=8.2 hz, 2H), 7.52 (d, j=8.6 hz, 1H), 7.38 (d, j=8.3 hz, 1H), 6.85 (s, 2H), 4.39 (t, j=6.7 hz, 2H), 4.18 (t, j=5.9 hz, 2H), 2.28 (p, j=5.9 hz, 2H), 1.64 (s, 9H).
Compound PLC-48 (4- (2- (3, 5-dichloro-4- (19, 19-difluoro-6,7,11,12,13,19-hexahydro-5H-18 l4,19l 4-benzo [3',4 ]']Cyclohepta [1',2':4,5]Pyrrolo [1,2-c]Benzo [3',4 ]']Cyclohepta [1',2':4,5]Pyrrolo [2,1-f][1,3,2]Diazaborane-9-yl) phenoxy) propyl) -1, 3-dioxo-2, 3-dihydro-1H-xantheno [2,1,9-def]Isoquinolin-9-yl) benzoic acid tert-butyl ester): compound PLC-48 in a similar manner to the procedure described above, a reaction was carried out from compound PLC-48.2 (0.1471 mmol102 mg), 1,4,5, 6-tetrahydrobenzo [6,7 ]]Cyclohepta [1,2-b ]]Pyrrole (Ex-7.3, 0.3090mmol,57mg and TFA (1% v/v), then DDQ (0.2501 mmol,57 mg) and 2 XEt 3 N (1.177 mmol,0.164 mL) and BF 3 .OEt 2 (1.765 mmol,0.218 mL) in anhydrous DCM (20 mL) at room temperature and then at 50deg.C. The crude reaction mixture was diluted with hexane and loaded onto-20 g silica gel in a cartridge. Purification by flash chromatography on silica gel (220 g, solid loading, equilibration of 10% etoac/hexanes, elution of 10% (2 CV) to 30% etoac/hexanes (40 CV)). The fractions containing the pure product were evaporated to dryness in vacuo. 80mg (50% yield) were obtained. MS (APCI): the chemical formula: calculated for C65H50BCl2F2N3O6 (m+h) =1088; actual measurement value: 1088.1H NMR (400 MHz, TCE) δH8.69 (d, J=7.8 Hz, 1H), 8.63 (d, J=8.3 Hz, 1H), 8.28 (d, J=2.2 Hz, 1H), 8.16-8.10 (m, 2H), 8.09 (d, J=8.1 Hz, 1H), 8.05 (t, J=4.7 Hz, 2H), 7.80 (dd, J=8.6, 2.1Hz, 1H), 7.77-7.71 (m, 2H), 7.51 (d, J=8.6 Hz, 1H), 7.42-7.33 (m, 5H), 7.33-7.25 (m, 2H), 7.01 (s, 2H), 6.47 (s, 2H), 4.44 (t, J=6.9 Hz, 2H), 4.22 (t, J=6.0 Hz), 7.77-7.71 (m, 2H), 7.51 (d, J=8.6 Hz, 1H), 7.42-7.33 (m, 2H), 7.44 (s, 2H), 4.44 (t, 9Hz, 2H), 4.22 (t, 2H).
Synthesis of Compound PLC-49:
compound PLC-49.1 (9- (4-butylphenyl) -2- (3-hydroxypropyl) -1H-xantheno [2,1,9-def]Isoquinoline-1, 3 (2H) -dione): compound PLC-49.1 in a similar manner to the above procedure, the compound PLC-38.1 (1.500 mmol,636 mg), (4-butylphenyl) boronic acid (3.00 mmol,534 mg), K 2 CO 3 (4.125 mmol,570 mg) and Pd (dppf) Cl 2 (0.105 mmol,77 mg) was synthesized in THF (30 mL)/DMF (6 mL)/water (3 mL) at 80 ℃. The precipitated compound was filtered off, washed with water and dried in vacuo. A tan solid, 655mg (92% yield) was obtained. MS (APCI): the chemical formula: calculated for C31H27NO4 (m+h) =478; actual measurement value: 478.1H NMR (400 MHz, TCE) δ8.66 (d, J=7.9 Hz, 1H), 8.61 (d, J=8.4 Hz, 1H), 8.26 (d, J=2.1 Hz, 1H), 8.06 (d, J=8.0 Hz, 1H), 7.79 (dd, J=8.6, 2.1Hz, 1H), 7.61 (d, J=7.9 Hz, 2H),7.48(d,J＝8.6Hz,1H),7.41-7.30(m,3H),4.34(t,J＝6.1Hz,2H),3.57(q,J＝6.0Hz,2H),3.24(t,J＝6.9Hz,1H),2.70(t,J＝7.7Hz,2H),2.06-1.92(m,2H),1.75-1.64(m,2H),1.42(h,J＝7.4Hz,2H),0.98(t,J＝7.3Hz,3H)。
Compound PLC-49.2 (3- (9- (4-butylphenyl) -1, 3-dioxo-1H-xantheno [2,1,9-def ] isoquinolin-2 (3H) -yl) propyl 4-methylbenzenesulfonate): a 100mL 2N round bottom flask was placed in an aluminum heating block and charged to a stir bar. The flask was fitted with a fin-type condenser/gas connector and a flow control valve. The system was purged with argon. To the flask were added PLC-49.1 (0.325 mmol,155 mg), 4-methylbenzenesulfonic anhydride (1.30 mmol,424 mg), and anhydrous DCE (20 mL). The reaction mixture was stirred at room temperature under argon and Et3N (1.463 mmol,0.20 ml) was added. The reaction mixture was stirred under argon, and the heating block was set to 90 ℃ and stirred at that temperature for 1 hour. The reaction was cooled to room temperature and loaded onto-15 g silica gel in a loader. Purification by flash chromatography on silica gel (80 g, solid loading, equilibration of 0% etoac/DCM, elution of 0% (2 CV) to 10% etoac/DCM (10 CV)). The product-containing fractions were evaporated to dryness in vacuo. A yellow solid was obtained, 157mg (77% yield). MS (APCI): the chemical formula: calculated value of C38H33NO6S (m+h) =632; actual measurement value: 632.1H NMR (400 MHz, TCE) delta 8.61 (d, J=7.9 Hz, 1H), 8.56 (d, J=8.4 Hz, 1H), 8.24 (d, J=2.2 Hz, 1H), 8.04 (d, J=8.1 Hz, 1H), 7.81-7.72 (m, 3H), 7.61 (d, J=8.1 Hz, 2H), 7.47 (d, J=8.6 Hz, 1H), 7.40-7.27 (m, 5H), 4.19 (dt, J=11.9, 6.6Hz, 4H), 2.70 (t, J=7.8 Hz, 2H), 2.42 (s, 3H), 2.19-2.07 (m, 2H), 1.76-1.64 (m, 2H), 1.42 (H, J=7.3 Hz, 2H), 0.98 (t, J=7.4 Hz, 3H).
Compound PLC-49.3 (4- (3- (9- (4-butylphenyl) -1, 3-dioxo-1H-xantheno [2,1,9-def ] isoquinolin-2 (3H) -yl) propoxy) -2, 6-dichlorobenzaldehyde): compound PLC-49.3 was synthesized from PLC-49.2 (0.122 mg,77 mg), 2, 6-dichloro-4-hydroxybenzaldehyde (0.365 mmol,70 mg) and K2CO3 (0.3411 mmol,47 mg) in anhydrous DMF (10 mL) in a similar manner to the procedure described above. The crude product was loaded onto-15 g of silica gel in a loader. Purification by flash chromatography on silica gel (80 g, solid loading, equilibration of 0% etoac/DCM, elution of 0% (2 CV) to 10% etoac/DCM (10 CV)). The product-containing fractions were evaporated to dryness in vacuo. A yellow solid, 60mg (76% yield) was obtained. MS (APCI): the chemical formula: calculated for C38H29Cl2NO5 (m+h) =650; actual measurement value: 650.1H NMR (400 MHz, TCE) δ10.37 (s, 1H), 8.63 (d, J=7.9 Hz, 1H), 8.58 (d, J=8.3 Hz, 1H), 8.26 (d, J=2.1 Hz, 1H), 8.06 (d, J=8.1 Hz, 1H), 7.79 (dd, J=8.6, 2.1Hz, 1H), 7.64-7.58 (m, 2H), 7.48 (d, J=8.6 Hz, 1H), 7.36 (d, J=7.2 Hz, 1H), 7.34 (d, J=7.1 Hz, 2H), 6.85 (s, 2H), 4.39 (t, J=6.8 Hz, 2H), 4.18 (t, J=6.0 Hz, 2H), 2.70 (t, J=7.8 Hz, 2H), 2.28 (p, J=6.6 Hz, 1H), 7.64-7.58 (m, 2H), 7.34 (d, J=7.2 Hz, 1H), 7.3Hz, 2H), 4.18 (d, 1.8 Hz, 2H), 3.7.7H (3 Hz, 2H).
Compound PLC-49 (9- (4-butylphenyl) -2- (3, 5-dichloro-4- (19, 19-difluoro-6,7,11,12,13,19-hexahydro-5H-18 l4,19l 4-benzo [3',4 ]']Cyclohepta [1',2':4,5]Pyrrolo [1,2-c]Benzo [3',4 ]']Cyclohepta [1',2':4,5]Pyrrolo [2,1-f][1,3,2]Diazaborane-9-yl) phenoxy) propyl) -1H-xantheno [2,1,9-def]Isoquinoline-1, 3 (2H) -dione): compound PLC-49 in a similar manner to Compound 32, from Compound PLC-49.3 (0.0922 mmol,60 mg), 1,4,5, 6-tetrahydrobenzo [6,7 ]]Cyclohepta [1,2-b ]]Pyrrole (Ex-7.3, 0.194mmol,36 mg) and TFA (0.2% v/v) were combined at room temperature followed by DDQ (0.157 mmol,36 mg) and 2 XEt 3 N (0.738 mmol,0.10 mL) and BF3.OEt2 (1.107 mmol,0.14 mL) were synthesized in anhydrous DCM (20 mL) at room temperature and then at 50deg.C. The crude reaction mixture was loaded onto-30 g silica gel in a loader. Purification by flash chromatography on silica gel (120 g, solid loading, equilibration of 0% etoac/hexanes, elution of 0% (2 CV) to 5% etoac/DCM (30 CV)). The product-containing fractions were evaporated to dryness in vacuo. 42mg of a dark red solid was obtained in 44% yield. MS (APCI): the chemical formula: calculated value of C64H50BCl2F2N3O4 (m+h) =1044; actual measurement value: 1044.1H NMR (400 MHz, TCE) delta 8.67 (d, J=7.8 Hz, 1H), 8.62 (d, J=8.3 Hz, 1H), 8.25 (d, J=2.1 Hz, 1H), 8.12-8.01 (m, 3H), 7.78 (dd, J=8.6, 2.1Hz, 1H), 7.65-7.56 (m, 2H), 7.48 (d, J=8.6 Hz, 1H), 7.42-7.24 (m, 9H), 7.01 (s, 2H), 6.47 (s, 2H), 4.45 (s, 2H), 4.22 (t, J=6.0 Hz, 6H), 2.70 (t, J=7.8 Hz, 2H), 2.64 (t, J=6.8 Hz, 4H), 2.42-2.23 (m, 6H), 2.11-1.97 (m, 9H), 7.01 (s, 2H), 6.47 (s, 2H), 4.22 (t, J=6.0 Hz, 6H), 2.70 (t, 2H), 2.64 (t, 3Hz, 3H).
Synthesis of Compound PLC-50:
compound PLC-50.1 (2- (3-hydroxypropyl) -9- (4- (pentyloxy) phenyl) -1H-xantheno [2,1,9-def]Isoquinoline-1, 3 (2H) -dione): compound PLC-50.1 in a similar manner to the procedure described above, starting from compound PLC-38.1 (1.500 mmol,636.0 mg), (4- (pentyloxy) phenyl) boronic acid (3.00 mmol,624 mg), K 2 CO 3 (4.125 mmol,570 mg) and Pd (dppf) Cl 2 (0.105 mmol,77 mg) was synthesized in THF (30 mL)/DMF (6 mL)/water (3 mL) at 80 ℃. The precipitated compound is filtered off, washed with water and dried in vacuo. A tan solid, 730mg (96% yield) was obtained. MS (APCI): the chemical formula: calculated for C32H29NO5 (m+h) =508; actual measurement value: 508.1H NMR (400 MHz, TCE) delta 8.66 (d, J=7.9 Hz, 1H), 8.61 (d, J=8.4 Hz, 1H), 8.21 (d, J=2.1 Hz, 1H), 8.06 (d, J=8.0 Hz, 1H), 7.75 (dd, J=8.6, 2.1Hz, 1H), 7.65-7.57 (m, 2H), 7.47 (d, J=8.6 Hz, 1H), 7.36 (d, J=8.4 Hz, 1H), 7.10-6.99 (m, 2H), 4.33 (t, J=6.1 Hz, 2H), 4.03 (t, J=6.6 Hz, 2H), 3.62-3.51 (m, 2H), 3.25 (t, J=6.9 Hz, 1H), 2.08-1.91 (m, 2H), 1.84 (d, J=8.4 Hz, 1H), 7.10-6.99 (m, 2H), 4.33 (t, J=6.1 Hz, 2H), 3.25 (t, 1.9 Hz, 1H).
Compound PLC-50.2 (3- (1, 3-dioxo-9- (4- (pentyloxy) phenyl) -1H-xantheno [2,1,9-def ] isoquinolin-2 (3H) -yl) propyl 4-methylbenzenesulfonate): compound PLC-50.2 was synthesized from compound PLC-50.1 (1.550 mmol,787 mg), 4-methylbenzenesulfonic anhydride (6.202 mmol,2024 mg) and Et3N (6.977 mmol,0.97 mL) in anhydrous DCE (20 mL) at 90℃in a similar manner to compound 46.2. The crude product was loaded onto-65 g of silica gel in a loader. Purification by flash chromatography on silica gel (120 g, solid loading, equilibration 0% etoac/DCM, elution 0% (2 CV) to 10% etoac/DCM (10 CV) to isocratic 10%). The product containing fractions were evaporated to dryness in vacuo to give 528mg (51% yield) of a yellow solid. MS (APCI): the chemical formula: calculated value of C39H35NO7S (m+h) =662; actual measurement value: 662.1H NMR (400 MHz, TCE) delta 8.58 (d, J=7.8 Hz, 1H), 8.53 (d, J=8.4 Hz, 1H), 8.17 (d, J=2.2 Hz, 1H), 8.00 (d, J=8.1 Hz, 1H), 7.79-7.75 (m, 2H), 7.73 (dd, J=8.8, 2.3Hz, 1H), 7.63-7.57 (m, 2H), 7.43 (d, J=8.6 Hz, 1H), 7.35-7.28 (m, 3H), 7.08-7.01 (m, 2H), 4.25-4.13 (m, 4H), 4.03 (t, J=6.6 Hz, 2H), 2.42 (s, 3H), 2.12 (p, J=6.6 Hz, 2H), 1.90-1.77 (m, 2H), 1.55-7.28 (m, 3H), 7.08-7.01 (m, 2H), 4.25-4.13 (m, 3H).
Compound PLC-50.3 (2, 6-dichloro-4- (3- (1, 3-dioxo-9- (4- (pentyloxy) phenyl) -1H-xantheno [2,1,9-def ] isoquinolin-2 (3H) -yl) propoxy) benzaldehyde): compound PLC-50.3 was synthesized from compound PLC-50.2 (0.180 mmol,119 mg), 2, 6-dichloro-4-hydroxybenzaldehyde (0.539 mmol,103 mg) and K2CO3 (0.503 mmol,70 mg) in anhydrous DMF (10 mL) in a similar manner to the procedure described above. The crude product was loaded onto-15 g of silica gel in a loader. Purification by flash chromatography on silica gel (80 g, solid loading, equilibration of 0% etoac/DCM, elution of 0% (2 CV) to 15% etoac/DCM (10 CV)). The product-containing fractions were evaporated to dryness in vacuo. A yellow solid was obtained, 103mg (84% yield). MS (APCI): the chemical formula: calculated for C39H31Cl2NO6 (m+h) =680; actual measurement value: 680.1H NMR (400 MHz, TCE) δ10.37 (s, 1H), 8.62 (d, J=7.9 Hz, 1H), 8.57 (d, J=8.3 Hz, 1H), 8.20 (d, J=2.2 Hz, 1H), 8.04 (d, J=8.1 Hz, 1H), 7.65-7.58 (m, 2H), 7.46 (d, J=8.6 Hz, 1H), 7.35 (d, J=8.4 Hz, 1H), 7.08-7.02 (m, 2H), 6.85 (s, 2H), 4.38 (t, J=6.8 Hz, 2H), 4.18 (t, J=6.0 Hz, 2H), 4.03 (t, J=6.6 Hz, 2H), 2.28 (p, J=6.5 Hz, 2H), 1.84 (p, J=6.7.7 Hz, 1.55-7.4 Hz, 1.35 (m, 2H), 4.38 (t, 6.8Hz, 2H).
Compound PLC-50 (2- (3, 5-dichloro-4- (19, 19-difluoro-6,7,11,12,13,19-hexahydro-5H-18 l4,19l 4-benzo [3',4' ] cyclohepta [1',2':4,5] pyrrolo [1,2-c ] benzo [3',4' ] cyclohepta [1',2':4,5] pyrrolo [2,1-f ] [1,3,2] diazaborane-9-yl) phenoxy) propyl) -9- (4- (pentyloxy) phenyl) -1H-xantheno [2,1,9-def ] isoquinoline-1, 3 (2H) -dione): compound 48 was synthesized from the compounds PLC-50.3 (0.150 mmol,102 mg), 1,4,5, 6-tetrahydrobenzo [6,7] cyclohepta [1,2-b ] pyrrole (Ex-7.3, 0.315mmol,58 mg) and TFA (0.25% v/v) at room temperature, followed by DDQ (0.255 mmol,58 mg) and 2X Et3N (1.199mmol, 0.17 mL) and BF3.OEt2 (1.798 mmol,0.22 mL) in anhydrous DCM (20 mL) at room temperature, then at 50 ℃. The crude reaction mixture was loaded onto-30 g silica gel in a loader. Purification by flash chromatography on silica gel (120 g, solid loading, equilibration and running 0% etoac/DCM isocratic). The product-containing fractions were evaporated to dryness in vacuo. A dark red solid, 127mg (79% yield) was obtained. MS (APCI): the chemical formula: calculated for C65H52BCl2F2N3O5 (m+h) =1074; actual measurement value: 1074.1H NMR (400 MHz, TCE) delta 8.67 (d, J=7.9 Hz, 1H), 8.61 (d, J=8.3 Hz, 1H), 8.20 (d, J=2.2 Hz, 1H), 8.11-8.00 (m, 3H), 7.74 (dd, J=8.6, 2.1Hz, 1H), 7.63-7.58 (m, 2H), 7.46 (d, J=8.6 Hz, 1H), 7.41-7.33 (m, 5H), 7.33-7.26 (m, 2H), 7.04 (d, J=8.9 Hz, 2H), 7.02 (s, 2H), 6.47 (s, 2H), 4.44 (t, J=6.9 Hz, 2H), 4.22 (t, J=6.6 Hz, 2H), 4.03 (t, J=6.6 Hz, 2H), 2.64.7.6 Hz, 1H), 7.41-7.33 (m, 2H), 7.33-7.26 (m, 2H), 7.04 (d, J=8.9 Hz, 2H), 7.02 (s, 2H), 4.47 (s, 2H), 4.44 (t, 3H), 4.22 (t, 6.22 Hz, 2H), 4.4.22 (t, 2H), 4.7.7 (1.1 Hz,1H, 1.7.7.7.7 (3H).
Synthesis of Compound PLC-51:
compound PLC-51.1 (6- (2-amino-4- (tert-butyl) phenoxy) -2- (3-hydroxypropyl) -1H-benzo [ de ] isoquinoline-1, 3 (2H) -dione): a 100mL 2N round bottom flask was placed in an aluminum heating block and charged to a stir bar. The flask was fitted with a fin-type condenser/gas connector and a flow control valve. The system was purged with argon. To the flask were added PLC-26.2 (2.559 mmol,925 mg), 3-aminopropan-1-ol (5.119 mmol, 0.3991 mL) and DMAP (0.768 mmol,94 mg), followed by 200 standard (proof) ethanol (20 mL). The reaction was stirred under argon and the heating block was set to 95 ℃. The reaction mixture was stirred at this temperature for 2 hours and then cooled to room temperature. The reaction mixture was quenched with 6H HCl (3 mL) and diluted with water (. About.100 mL). The resulting precipitate was filtered off and washed with water. The precipitate was dried in vacuo to give a tan solid in quantitative yield. MS (APCI): the chemical formula: calculated for C25H26N2O4 (m+h) =419; actual measurement value: 419.1H NMR (400 MHz, TCE) δ8.80 (dd, J=8.4, 1.2Hz, 1H), 8.67 (dd, J=7.3, 1.2Hz, 1H), 8.46 (d, J=8.3 Hz, 1H), 7.84 (dd, J=8.4, 7.3Hz, 1H), 7.02-6.92 (m, 3H), 6.87 (dd, J=8.4, 2.2Hz, 1H), 4.31 (t, J=6.2 Hz, 2H), 3.56 (q, J=5.0 Hz, 2H), 1.97 (p, J=6.0 Hz, 2H), 1.35 (s, 9H).
Compound PLC-51.2 (9- (tert-butyl) -2- (3-hydroxypropyl) -1H-xantheneXantho [2,1,9-def]Isoquinoline-1, 3 (2H) -dione): a40 mL vial was filled with a stir bar. Addition of NaNO to vials 2 (11.29 mmol,779 mg) and water (4 mL). The vials were stirred in an ice-water bath at 0 ℃. A separate 40mL vial was also filled with a stir bar. To this vial was added compound PLC-51.1 (1.505 mmol,630 mg), acetic acid (12 mL) and concentrated HCl (7.527 mmol, mL). The vials were stirred at room temperature for several minutes, then placed in an ice-water bath and stirred at 0 ℃ for 1 minute. NaNO was added to the mixture under stirring at 0 ℃ for 10 minutes 2 An aqueous solution was added to the vial. The diazonium solution is stirred at 0℃for 1 hour. Meanwhile, a 250mL 2N round bottom flask was fitted with a fin condenser, addition funnel and stirrer bar. CuSO was added to the flask 4 .5H 2 O (10.237 mmol, 2.552 g) and water (35 mL). The solution was stirred at room temperature. About 15 minutes before the end of the 1 hour diazotization, the copper sulfate solution is heated to 130 ℃ (heating block temperature). The diazonium solution was transferred to the addition funnel and added to the reaction mixture with high speed stirring over about 15 minutes. The reaction mixture was stirred for an additional 1 minute and then placed in a room temperature water bath. Once the reaction cooled to room temperature, the product was isolated by filtration. The crude product is a mixture of the desired alcohol and acetate. The crude product was dispersed in methanol and treated with excess K2CO3 at 60 ℃ to cleave the ester. The reaction was diluted with water and the product was filtered off and washed with water. The crude product was dissolved in DCM and evaporated in vacuo onto silica gel. Purification by flash chromatography on silica gel (120 g, solid loading, equilibrated 0% EtOAc/DCM, eluting 0% (2 CV) 75% EtOAc/DCM (20 CV)). The product-containing fractions were evaporated to dryness in vacuo. A yellow solid, 379mg (37% yield) was obtained. MS (APCI): the chemical formula: calculated value of C25H23NO4 (m+h) =419; actual measurement value: 419.1H NMR (400 MHz, TCE) delta 8.65 (d, J=7.8 Hz, 1H), 8.60 (d, J=8.4 Hz, 1H), 8.07 (d, J=2.3 Hz, 1H), 8.01 (d, J=8.0 Hz, 1H), 7.63 (dd, J=8.7, 2.2Hz, 1H), 7.37 (d, J=8.7 Hz, 1H), 7.34 (d, J=8.3 Hz, 1H), 4.33 (t, J=6.1 Hz, 2H), 3.57 (q, J=6.1 Hz, 2H), 3.26 (t, J=6.9 Hz, 1H), 1.98 (p, J=5.9 Hz, 2H), 1.44 (s, 9H).
Compound PLC-51.3 (2- (3-bromopropyl) -9- (tert-butyl) -1H-xantheno [2,1,9-def ] isoquinoline-1, 3 (2H) -dione): a 100mL 2N round bottom flask was placed in an aluminum heating block and charged to a stir bar. The flask was fitted with a fin-type condenser/gas connector and a flow control valve. The system was purged with argon. To the flask were added PLC-51.2 (0.4813 mmol,194 mg) and carbon tetrabromide (0.725 mmol,240 mg), followed by the addition of anhydrous DCE (20 mL). The reaction mixture was stirred at room temperature under argon and triphenylphosphine (0.725 mmol,190 mg) was added. The reaction mixture was stirred at room temperature for 30 minutes. The reaction mixture was loaded onto-15 g of silica gel in a loader. Purification by flash chromatography on silica gel (120 g, solid loading, equilibration of 0% etoac/DCM, elution of 0% (2 CV) to 10% etoac/DCM (20 CV)). The product-containing fractions were evaporated to dryness in vacuo. A yellow solid, 149mg (66% yield) was obtained. MS (APCI): the chemical formula: calculated for C25H22BrNO3 (m+h) =464; actual measurement value: 464.
Compound PLC-51 (9- (tert-butyl) -2- (3, 5-dichloro-4- (19, 19-difluoro-6,7,11,12,13,19-hexahydro-5H-18 l4,19l 4-benzo [3',4' ] cyclohepta [1',2':4,5] pyrrolo [1,2-c ] benzo [3',4' ] cyclohepta [1',2':4,5] pyrrolo [2,1-f ] [1,3,2] diazaborane-9-yl) phenoxy) propyl) -1H-xantheno [2,1,9-def ] isoquinoline-1, 3 (2H) -dione: compound PLC-51 was synthesized from the compounds PLC-51.3 (0.399mmol, 148 mg), 3, 5-dichloro-4- (19, 19-difluoro-6,7,11,12,13,19-hexahydro-5H-18 l4,19l 4-benzo [3',4' ] cyclohepta [1',2':4,5] pyrrolo [1,2-c ] benzo [3',4' ] cyclohepta [1',2':4,5] pyrrolo [2,1-f ] [1,3,2] diazaborane-9-yl) phenol (PLC-1.3, 0.446mmol,261 mg) and K2CO3 (0.386 mmol,53 mg) in anhydrous DMF (10 mL) in a similar manner to the procedure described above. The crude reaction mixture was diluted with water and the product was filtered off. The precipitate was dissolved in DCM and evaporated to dryness in vacuo. The product was dissolved in DCM, loaded onto-20 g of silica gel in a loader, and purified by flash chromatography on silica gel (120 g, solid loading, equilibration 0% etoac/DCM, elution 0% (2 CV) to 5% etoac/DCM (50 CV)). The product-containing fractions were evaporated to dryness in vacuo. A dark red solid, 153mg (50% yield) was obtained. MS (APCI): the chemical formula: calculated for C58H46BCl2F2N3O4 (m+h) =968; actual measurement value: 968.1H NMR (400 MHz, TCE) delta 8.67 (d, J=7.9 Hz, 1H), 8.60 (d, J=8.3 Hz, 1H), 8.10-7.98 (m, 4H), 7.62 (dd, J=8.8, 2.2Hz, 1H), 7.40-7.25 (m, 8H), 7.02 (s, 2H), 6.48 (s, 2H), 4.43 (t, J=7.0 Hz, 2H), 4.21 (t, J=6.0 Hz, 2H), 2.70-2.59 (m, 4H), 2.33 (t, J=6.7 Hz, 6H), 2.12-1.98 (m, 4H), 1.44 (s, 9H).
Synthesis of Compound PLC-52:
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compound PLC-52.1 (5, 11-dibromo-1 h,3 h-isochromeno [6,5,4-mna ] xanthene-1, 3-dione): a 2L 2N round bottom flask was charged to a stir bar and fitted with a long fin condenser. 1H, 3H-Isochromo [6,5,4-mna ] xanthene-1, 3-dione (Ex-1.3 synthesized according to literature: RSC adv.,2014,4,53072-53078) (34.688 mmol,10.00 g) was added to the flask followed by o-dichlorobenzene (1000 mL). The reaction mixture was stirred at room temperature and Br2 (416.26 mmol,21.3 ml) was added. The second neck was plugged and the reaction mixture was heated during the weekend with an aluminum heat block open to air at 75 ℃. The reaction mixture was cooled to room temperature and the solid was filtered off. The filtrate was diluted with hexane (-20% by volume) and the second precipitate was filtered off. Both precipitates were dried in vacuo at 100 ℃. Orange solid, total 10.866g (69.9% yield). Both have similar LCMS and NMR. MS (APCI): the chemical formula: calculated for C18H6Br2O4 (m+h) =445; actual measurement value: 445.1H NMR (400 MHz, TCE) δ9.47 (dd, J=8.4, 1.5Hz, 1H), 8.76 (d, J=14.2 Hz, 2H), 7.72-7.63 (m, 1H), 7.56 (dd, J=8.3, 1.4Hz, 1H), 7.46 (ddd, J=8.5, 6.7,1.9Hz, 1H).
Compound PLC-52.2 (2- (4- (5, 11-dibromo-1, 3-dioxo-1H-xantheno [2,1,9-def ] isoquinolin-2 (3H) -yl) phenyl) acetic acid): compound PLC-52.2 was synthesized from PLC-52.1 (7.000 mmol,3.136 g), 2- (4-aminophenyl) acetic acid (14.00 mmol,2.117 g) and DMAP (2.100 mmol,257 mg) in anhydrous DMF (65 mL) at 160℃in a similar manner to the procedure described above. The crude reaction mixture was cooled to 0deg.C, quenched with 6N HCl (5 mL) and diluted with water (up to 350 mL). The precipitate is filtered off and washed with water. The product was dried by suction and used for the next reaction without further purification. Assume a 100% yield. MS (APCI): the chemical formula: calculated for C26H13Br2NO5 (m+h) =578; actual measurement value: 578.
Compound PLC-52.3 (2- (4- (1, 3-dioxo-5, 11-bis (4- (trifluoromethyl) phenyl) -1H-xantheno [2,1,9-def ] isoquinolin-2 (3H) -yl) phenyl) acetic acid): compound PLC-52.3 was synthesized from compound PLC-52.2 (3.500 mmol,2.034 g), (4- (trifluoromethyl) phenyl) boronic acid (14.00 mmol,2.659 g), K2CO3 (19.25 mmol,2.661 g) and Pd (dppf) Cl2 (0.0245 mmol, 178 mg) in THF (/ 60 mL), DMF (12 mL) and water (6 mL) under an argon atmosphere at 80 ℃. The crude reaction mixture was evaporated to dryness in vacuo, dissolved in DCM, and evaporated in vacuo onto-35 g of flash silica gel. Purification by flash chromatography on silica gel (220 g, equilibrated 0% EtOAc/DCM, eluted 0% (10 CV) to 15.3% EtOAc/DCM (15.3 CV) to 40% EtOAc/DCM (10 CV) to isocratic 40% EtOAc/DCM). EtOAc contained 0.1% v/v TFA. The product-containing fractions were evaporated to dryness in vacuo. A tan solid was obtained, 2.000g (80.3% from compound 80.1 (1655-11)). MS (APCI): the chemical formula: calculated for C40H21F6NO5 (m+h) =710; actual measurement value: 710.1H NMR (400 MHz, DMSO). Delta.12.44 (s, 1H), 8.47 (s, 1H), 8.23 (s, 1H), 8.02 (d, J=8.1 Hz, 2H), 7.97-7.88 (m, 4H), 7.75 (d, J=8.0 Hz, 2H), 7.49-7.37 (m, 3H), 7.31 (d, J=8.2 Hz, 1H), 7.30-7.24 (m, 2H), 7.02-6.91 (m, 2H), 3.68 (s, 2H).
Compound PLC-52.4: to a solution of compound PLC-29 (113 mg,0.1 mmol) in 8mL of anhydrous DCM and 3mL of DMF was added NBS (106 mg,0.6 mmol). The mixture was heated at 60 ℃ overnight. The resulting mixture was diluted with 100mL of DCM, washed with water (2×50 mL), loaded onto silica gel, and purified by flash chromatography using an eluent of DCM/EA (0% to 10% EA). The main peak was collected. After removal of the solvent and trituration with methanol, after filtration and drying in air, a reddish brown solid was obtained (80 mg, 58% yield). LCMS (APCI-): calculated for C66H38BBr3Cl2F5N3O 5: 1364.98 (M-); actual measurement value: 1365.
compound PLC-52.5: a mixture of compound PLC-52.4 (54 mg,0.039 mmol), 4-n-butylphenylboronic acid (42 mg,0.236 mmol), pd (PPh 3) 4 (14 mg,0.012 mmol) and potassium carbonate (32 mg,0.236 mmol) in THF/DMF/water (10 mL/2mL/1 mL) was degassed and heated at 80℃for 6 hours. The resulting mixture was diluted with 100mL of DCM, dried loaded on silica gel and purified by flash chromatography using an eluent of hexane/DCM (0% to 50% DCM). The first major peak was collected and the solvent was removed to give the desired product as a red solid (10 mg, 30% yield). LCMS (APCI-): calculated for C53H49BCl2F2N 2O: 848.33 (M-); actual measurement value: 848.1H NMR (400 MHz, TCE) δ8.02 (bs, 2H), 7.36-7.14 (m, 6H), 6.73 (m, 8H), 4.42 (s, 1H), 2.61 (bs, 4H), 2.39-2.31 (m, 4H), 1.86 (s, 8H), 1.37 (p, J=7.6 Hz, 4H), 1.30-1.15 (m, 6H), 0.85 (t, J=7.3 Hz, 6H).
Compound PLC-52: a mixture of compound PLC-52.5 (10 mg,0.012 mmol), (2- (4- (1, 3-dioxo-5, 11-bis (4- (trifluoromethyl) phenyl) -1H-xantho [2,1,9-def ] isoquinolin-2 (3H) -yl) phenyl) acetic acid) (16 mg,0.022 mmol), DMAP/TsOH (5 mg,0.017 mmol), DIC (0.05 mL,0.31 mmol) in 5mL anhydrous DCM was stirred at room temperature overnight. The resulting mixture was loaded on silica gel and purified by flash chromatography using an eluent of hexane/DCM (0% to 100% DCM). The desired main peak was collected and after removal of the solvent and trituration with MeOH, a dark brown solid was obtained (10 mg, 54% yield). LCMS (APCI-): calculated for C93H68BCl2F8N3O 5: 1539.45 (M-); actual measurement value: 1539.1H NMR (400 MHz, TCE) delta 8.64 (s, 1H), 8.40 (s, 1H), 8.03 (s, 2H), 7.83 (d, J=8.2 Hz, 2H), 7.81-7.74 (m, 4H), 7.59 (d, J=8.0 Hz, 2H), 7.46 (d, J=8.2 Hz, 2H), 7.39-7.17 (m, 11H), 7.02 (d, J=8.0 Hz, 1H), 6.95-6.50 (m, 10H), 3.78 (s, 2H), 2.62 (s, 4H), 2.41-2.30 (m, 4H), 1.87 (s, 8H), 1.41 (p, J=7.4 Hz, 4H), 1.32-1.21 (m, 4H), 0.87 (t, J=7.3 Hz, 6H).
Synthesis of Compound PLC-53
Compound PLC-53.1 (9- (6- (2-amino-4- (tert-butyl) phenoxy) -2- (2-hydroxyethyl) -1H-benzo [ de ] isoquinoline-1, 3 (2H) -dione) compound PLC-53.1 was synthesized from PLC-26.2 (8.827 mmol,3.190 g), ethanolamine (17.65 mmol,1.066 mL) and DMAP (2.644 mmol,324 mg) in a similar manner to the procedure described above, followed by 200 standard ethanol (70 mL) filtering off the crude precipitate, dissolving in acetone, and evaporating in vacuo to dryness to give a tan solid, 2.777g (78% yield) MS (APCI) of formula C24H24N2O4 (m+h) calculated = 405, found values 405.1H NMR (400 mhz, tce) delta 8.80 (dd, j=8.4, 1.2H), 8.67 (dd, j=7.3, 1.46 hz), 8.46 hz (3 hz), 8.7.7H (2 hz), 3.7.46 hz (2H), 3.7.7H), 7.7H (2 hz), 3H (3H), 7.7.46 hz (3H), 3H (2H), 39H) and (3H) calculated values = 405.
Compound PLC-53.2 (9- (tert-butyl) -2- (2-hydroxyethyl) -1H-xantheno [2,1,9-def ] isoquinoline-1, 3 (2H) -dione): compound PLC-53.2 was synthesized from compound PLC-53.1 (6.863 mmol,2.776 g), naNO2 (51.470 mmol,3.552 g), concentrated HCl (34.317 mmol,2.83 mL) and CuSO4.5H2O (46.67 mmol,11.653 g) in a similar manner to the procedure described above. The crude product was-10% acetate. It was cleaved with K2CO3 in the same manner as described above. The crude cleavage mixture was dissolved in acetone and evaporated onto-20 g of silica gel and placed in a loader. Purification by flash chromatography on silica gel (120 g, solid loading, equilibration 0% etoac/DCM, elution (2 CV) to 85% etoac/DCM (20 CV)). The product-containing fractions were evaporated to dryness in vacuo. A yellow solid, 732mg (27% yield) was obtained. MS (APCI): the chemical formula: calculated value of C24H21NO4 (m+h) =388; actual measurement value: 388.
compound PLC-53.3 (4- (2- (9- (tert-butyl) -1, 3-dioxo-1H-xantheno [2,1,9-def ] isoquinolin-2 (3H) -yl) ethoxy) -2, 6-dichlorobenzaldehyde): compound PLC-53.2 (0.200 mmol,78 mg) and 2, 6-dichloro-4-hydroxybenzaldehyde (0.260 mmol,50 mg) were added to a 40mL screw-cap vial followed by anhydrous DCE (10 mL) and a stirring bar. The reaction mixture was stirred at room temperature, and DEAD (0.300 mmol,0.137 mL) and PPh3 (0.300 mmol,79 mg) were added. The reaction mixture was stirred at room temperature for 60 minutes. Additional DEAD (0.100 mmol,0.046 mL) and PPh3 (0.100 mmol,26 mg) were added and stirring continued overnight at room temperature. The crude reaction mixture was loaded onto-20 g silica gel in a loader. Purification by flash chromatography on silica gel (80 g, solid loading, equilibration of 0% etoac/DCM, elution of 0% (2 CV) to 10% etoac/DCM (15 CV)). MS (APCI): the chemical formula: calculated for C31H23Cl2NO5 (m+h) =560; actual measurement value: 560.1H NMR (400 MHz, TCE) δ10.36 (s, 1H), 8.66 (d, J=7.9 Hz, 1H), 8.60 (d, J=8.5 Hz, 1H), 8.06 (d, J=2.3 Hz, 1H), 8.01 (d, J=8.0 Hz, 1H), 7.63 (dd, J=8.7, 2.2Hz, 1H), 7.37 (d, J=8.8 Hz, 1H), 7.34 (d, J=8.4 Hz, 1H), 6.99 (s, 2H), 6.95 (d, J=14.5 Hz, 1H), 4.64 (t, J=6.2 Hz, 2H), 4.39 (t, J=6.2 Hz, 2H), 1.44 (s, 9H).
Compound PLC-53 (9- (tert-butyl) -2- (2- (4- (19, 19-difluoro-6,7,11,12,13,19-hexahydro-5H-18 l4,19l 4-benzo [3',4' ] cyclohepta [1',2':4,5] pyrrolo [1,2-c ] benzo [3',4' ] cyclohepta [1',2':4,5] pyrrolo [2,1-f ] [1,3,2] diazaborane-9-yl) -3, 5-dimethylphenoxy) ethyl) -1H-xantheno [2,1,9-def ] isoquinoline-1, 3 (2H) -dione): compound PLC-53 was synthesized from compound 53.3 (0.186 mmol,104 mg), 1,4,5, 6-tetrahydrobenzo [6,7] cyclohepta [1,2-b ] pyrrole (Ex-7.3, 0.371mmol,68 mg) and pTsOH.H2O (0.0186 mmol,3.5 mg) in a similar manner to compound 32, then DDQ (0.241 mmol,55 mg) and 2X Et3N (1.480 mmol,0.210 mL) and BF3.OEt2 (2.227 mmol,0.280 mL) in anhydrous DCM (20 mL) at room temperature, then at 50 ℃. The crude reaction mixture was diluted with hexane and then loaded onto-20 g of silica gel in a loader. Purification by flash chromatography on silica gel (80 g, solid loading, equilibration of 0% etoac/hexanes, elution of 0% (2 CV) to 75% etoac/hexanes (30 CV)). The product-containing fractions were evaporated to dryness in vacuo. The crude product was triturated and dried in vacuo. A dark red solid, 138mg (78% yield) was obtained. MS (APCI): the chemical formula: calculated value of C59H50BF2N3O4 (m+h) =954; actual measurement value: 954.1H NMR (400 MHz, TCE) delta 8.70 (d, J=7.9 Hz, 1H), 8.64 (d, J=8.4 Hz, 1H), 8.10-7.99 (m, 4H), 7.63 (dd, J=8.7, 2.2Hz, 1H), 7.42-7.32 (m, 6H), 7.32-7.24 (m, 2H), 7.14 (s, 2H), 6.43 (s, 2H), 4.70 (t, J=6.2 Hz, 2H), 4.42 (t, J=6.3 Hz, 2H), 2.62 (t, J=6.6 Hz, 4H), 2.30 (s, 4H), 2.11-1.96 (m, 4H), 1.44 (s, 9H).
EXAMPLE 10 preparation of the Filter layer
The glass substrate is prepared essentially in the following manner. A 1.1mm thick glass substrate having dimensions of 1 inch x 1 inch was cut to size. The glass substrate was then washed with detergent and Deionized (DI) water, rinsed with fresh DI water, and sonicated for about 1 hour. The glass was then immersed in isopropyl alcohol (IPA) and sonicated for about 1 hour. The glass substrate was then immersed in acetone and sonicated for about 1 hour. The glass was then removed from the acetone bath and dried with nitrogen at room temperature.
A 20 wt.% solution of poly (methyl methacrylate) (PMMA) (average m.w. of 120,000 as measured by GPC, from millipore sigma, burlington, MA, USA) copolymer in cyclopentanone (99.9% purity) was prepared. The copolymer prepared was stirred at 40℃overnight. [ PMMA ] CAS 9011-14-7; [ cyclopentanone ] CAS 120-92-3
The 20% PMMA solution (4 g) prepared above was added to 3mg of the photoluminescent compound prepared as described above in a sealed container and mixed for about 30 minutes. The PMMA/luminophore solution was then spin coated onto the prepared glass substrate at 1000RPM for 20 seconds, followed by spin coating at 500RPM for 5 seconds. The thickness of the resulting wet coating was about 10 μm. Prior to spin coating, the samples were covered with aluminum foil to protect them from exposure to light. Three samples were prepared in this manner for each of the emission/FWHM and quantum yield. The spin-coated samples were baked in a vacuum oven at 80 ℃ for 3 hours to evaporate the remaining solvent.
A 1 inch x 1 inch sample was inserted into a Shimadzu, UV-3600UV-VIS-NIR spectrophotometer (Shimadzu Instruments, inc., columbia, MD, USA). All plant operations were performed in a nitrogen filled glove box. The resulting absorption/emission spectrum of PLC-1 is shown in FIG. 1, the resulting absorption/emission spectrum of PLC-2 is shown in FIG. 2, and the resulting absorption/emission spectrum of PLC-3 is shown in FIG. 3.
Fluorescence spectra of 1 inch by 1 inch film samples prepared as described above were determined using a Fluorolog spectrofluorometer (Horiba Scientific, edison, NJ, USA), with excitation wavelengths set to the respective maximum absorption wavelengths. The maximum emission and FWHM are shown in table 1.
Quantum yields of 1 inch by 1 inch samples prepared as described above were determined using a Quantarus-QY spectrophotometer (Hamamatsu Inc., campbell Calif., USA) excited at the respective maximum absorption wavelengths. The results are reported in table 1.
The results of film characterization (absorption peak wavelength, FWHM and quantum yield) are shown in table 1 below.
TABLE 1
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Claims (17)

1. A photoluminescent compound comprising:
a blue light absorbing donor chromophore, wherein the donor chromophore comprises a naphthalimide derivative;
ligating the complex; and
A ring-locked boron-dipyrromethene (BODIPY) moiety;
wherein the linking complex covalently links the donor chromophore to the naphthalimide derivative and the ring-locked BODIPY moiety, wherein the naphthalimide derivative absorbs blue light energy at a first excitation wavelength and transfers energy to the ring-locked BODIPY moiety, wherein the ring-locked BODIPY moiety emits light energy at a second, longer wavelength, and wherein the photoluminescence complex has an emission quantum yield greater than 80%.
2. The photoluminescent complex of claim 1, wherein the naphthalimide derivative of the donor chromophore has the general formula:
wherein Y is O or S; wherein R is 7 And R is 8 Independently H, substituted or unsubstituted aryl, or-CF 3 The method comprises the steps of carrying out a first treatment on the surface of the And wherein R is 9 Independently H, substituted or unsubstituted aryl, or C 1 -C 5 An alkyl group.
3. The photoluminescent compound of claim 1, wherein the photoluminescent compound has the general formula:
wherein R is 1 And R is 2 H, C independently 1 -C 3 Alkyl or substituted aryl; wherein R is 3 And R is 4 H, F, br, or-CF independently 3 The method comprises the steps of carrying out a first treatment on the surface of the Wherein R is 5 And R is 6 H, C independently 1 -C 3 Alkyl, halide, or C 1 -C 3 An alkoxy group; and wherein each X is independently C 1 -C 3 Alkyl or spiro-cycloalkyl, wherein L is the linking complex and Z is the donor chromophore.
4. A photoluminescent compound according to claim 3, wherein L is a substituted or unsubstituted ester.
5. A photoluminescent compound according to claim 3, wherein L is a substituted ether or an unsubstituted ether.
6. The photoluminescent complex of claim 1, 3, or 4, wherein the linking complex is an unsubstituted ester; wherein the unsubstituted ester comprises one of the following structures:
7. the photoluminescent complex of claim 1, 3, or 4, wherein the linking complex is a substituted ester; wherein the substituted ester comprises one of the following structures:
8. the photoluminescent complex according to claim 1, 3 or 5, wherein the linking complex is an unsubstituted ether and/or a substituted ether; wherein the unsubstituted ether and/or substituted ether comprises one of the following structures:
9. the photoluminescent compound of claim 1, 2, 3, 4, 5, 6, 7, or 8, wherein the photoluminescent compound comprises one of the following structures:
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or any combination thereof.
10. A color conversion film, comprising:
a transparent substrate layer;
a color conversion layer, wherein the color conversion layer comprises a resin matrix; and at least one photoluminescent composite according to claim 1, 2, 3, 4, 5, 6, 7, 8, or 9 dispersed in the resin matrix.
11. The color conversion film of claim 10, further comprising a singlet oxygen quencher.
12. The color conversion film of claim 10, further comprising a radical scavenger.
13. The color conversion film of claim 10, wherein the film has a thickness between 10 μιη and 200 μιη.
14. The color conversion film of claim 10, wherein the film absorbs light in a wavelength range of about 400nm to about 480nm and emits light in a wavelength range of about 590nm to about 650 nm.
15. A method of making a color conversion film, the method comprising:
dissolving the photoluminescent composite of claim 1, 2, 3, 4, 5, 6, 7, 8, or 9 and a binder resin in a solvent; and
the mixture is applied to a transparent substrate layer.
16. A backlight unit comprising the color conversion film according to claim 10, 11, 12, 13, or 14.
17. A display device comprising the backlight unit according to claim 16.
CN202280036055.0A 2021-09-27 2022-09-23 Boron-containing cyclic light-emitting compound and color conversion film comprising the same Pending CN117396580A (en)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US63/248,863 2021-09-27
US202163278944P 2021-11-12 2021-11-12
US63/278,944 2021-11-12
PCT/US2022/076912 WO2023049828A1 (en) 2021-09-27 2022-09-23 Boron-containing cyclic emissive compounds and color conversion film containing the same

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