CN112110863A - Sulfonyl fluoride compound, preparation method thereof and method for preparing sulfonamide compound through sulfonyl fluoride compound - Google Patents

Sulfonyl fluoride compound, preparation method thereof and method for preparing sulfonamide compound through sulfonyl fluoride compound Download PDF

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CN112110863A
CN112110863A CN202010879059.8A CN202010879059A CN112110863A CN 112110863 A CN112110863 A CN 112110863A CN 202010879059 A CN202010879059 A CN 202010879059A CN 112110863 A CN112110863 A CN 112110863A
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李乐
魏明杰
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Sun Yat Sen University
National Sun Yat Sen University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/32—One oxygen, sulfur or nitrogen atom
    • C07D239/42—One nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
    • C07C309/78—Halides of sulfonic acids
    • C07C309/86—Halides of sulfonic acids having halosulfonyl groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C309/88—Halides of sulfonic acids having halosulfonyl groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing nitrogen atoms, not being part of nitro or nitroso groups, bound to the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/74—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/48—Two nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links

Abstract

The invention discloses a novel method for preparing sulfonamide compounds, in particular Fedratinib, and provides a novel intermediate and a preparation method of the intermediate. The preparation method disclosed by the invention is simple and safe to operate, does not need special purification equipment, can obtain reagents and raw materials for reaction in a commercially available manner, is mild in reaction condition, environment-friendly and pollution-free, high in product yield, high in purity and few in byproducts, can be used for quickly preparing different types of sulfonamides, and provides a brand-new method for quickly screening active sulfonamide compounds in medicinal chemistry.

Description

Sulfonyl fluoride compound, preparation method thereof and method for preparing sulfonamide compound through sulfonyl fluoride compound
Technical Field
The invention relates to the technical field of drug synthesis, in particular to a sulfonyl fluoride compound, a preparation method thereof and a novel method for preparing a sulfonamide compound from the sulfonyl fluoride compound.
Background
Due to the special biological activity of sulfonamide compounds, the sulfonamide compounds are receiving more and more attention from researchers, and are widely applied to medicines and pesticides, such as antibacterial agents, anticancer agents, antidiabetic agents, anti-AIDS agents, insecticides, and the like. Different sulfonamides in the medicine act on different targets to generate different biological activities, and the biological activities need to be rapidly screened in batches in the research and development of new medicines, so that the later functionalization of the medicines and the rapid preparation of series sulfonamide compounds are particularly important.
The sulfonamide drug Fedratinib (N-tert-butyl-3- [ (5-methyl-2- { [4- (2-pyrrolidin-1-ylethoxy) phenyl ] amino } pyrimidin-4-yl) amino ] benzenesulfonamide) is a high-selectivity JAK2 inhibitor, compared with family members JAK1, JAK3 and TYK2, it has higher inhibitory effect on JAK2, is entitled by FDA to orphan drug for treating secondary and primary myelofibrosis, is applied to market by New base company, is approved to market by US food and drug administration in 8 months of 2019, is used for treating primary or secondary (after polycythemia vera or after primary thrombocythemia) myelofibrosis adult patients at medium-risk-2 or high-risk, and provides a new once-a-day oral treatment option for the patients.
The currently reported preparation method of Fedratinib is mainly a related synthesis method reported in WO2012061833A1, US8133900B2 and the like. Specifically, benzene sulfonyl chloride compounds and tert-butylamine are adopted to generate sulfonamide compounds, then benzene sulfonyl tert-butylamine intermediates are synthesized through a route A and a route B, and the benzene sulfonyl tert-butylamine intermediates are further reacted with aniline compounds to obtain final products.
Figure BDA0002653547590000021
In the prior art, a benzenesulfonyl tert-butylamine intermediate needs to be prepared firstly, and then the intermediate is subjected to microwave or heating to obtain a final product, or a reactant is acidified and then alkalized and then reacts with the intermediate to obtain the final product. In the prior art, when different amines are used for replacing tert-butylamine to prepare Fedratinib analogues, different A or B type intermediates need to be prepared again, the steps are long, the process is complicated, and the efficiency is low. Therefore, there is a need to find a simple and efficient method that can modify the structure of the amine on the sulfonamide functionality at a later stage.
Disclosure of Invention
The invention provides a sulfonyl fluoride compound, a preparation method thereof and application of the sulfonyl fluoride compound in preparation of sulfonamide compounds. The inventor creatively provides a novel synthesis strategy for rapidly preparing sulfonamide compounds through sulfonyl fluoride intermediates. This strategy is particularly effective for the synthesis of Fedratinib and its analogs. This synthesis strategy constructs a compound of formula 4 by efficiently coupling a compound of formula 2 with a compound of formula 3, then constructs a compound of formula 6 by nucleophilic substitution or coupling a compound of formula 4 with a compound of formula 5, and finally constructs Fedratinib and its analogs from a compound of formula 6 and a compound of formula 7 by nucleophilic substitution. By adopting the synthesis strategy, different kinds of sulfonamide compounds can be rapidly prepared.
In a first aspect, the present invention provides a compound of formula (4) or a salt thereof:
Figure BDA0002653547590000022
wherein X is F, Cl, Br or I, Z is H, C1-C10Alkyl radical, C1-C10Alkoxy, F, Cl, Br, I, CN, NO2、CF3Or C2-C10Ester group, G1、G2、G3、G4、G5Is N or CR ', wherein R' is selected from H, C1-C10Alkyl radical, C1-C10Alkoxy, CN, CF3、C2-C10Ester group, NO2F, Cl, Br or I, and G1To G5At least one of which is not N; y is F, Cl, Br, I, C1-C10Alkyl radical, C1-C10Alkoxy, CN, NO2、CF3Amino or C2-C10An ester group, and n is 0, 1,2, 3 or 4.
Preferably, in the formula (4)Wherein X is F, Cl or Br, Z is H, C1-C6Alkyl radical, C1-C6Alkoxy, F, Cl, Br, I, CN, NO2、CF3Or C2-C6Ester group, G1、G2、G3、G4、G5Is N or CR ', wherein R' is selected from H, C1-C6Alkyl radical, C1-C6Alkoxy, CN, CF3、C2-C6Ester group, NO2F, Cl, Br or I, and G1To G5At least two of which are not N; y is F, Cl, Br, I, C1-C6Alkyl radical, C1-C6Alkoxy, CN, NO2、CF3Amino or C2-C6An ester group, and n is 0, 1,2, 3 or 4.
Further preferably, the compound of formula (4) is selected from:
Figure BDA0002653547590000031
Figure BDA0002653547590000041
in a second aspect, the present invention provides a process for the preparation of a compound of formula (4), which comprises reacting a compound of formula (2) with a compound of formula (3) via a nucleophilic substitution or coupling reaction to give a compound of formula (4):
Figure BDA0002653547590000042
wherein, X, Z, G1、G2、G3、G4、G5Y and n are as defined for formula (4).
Preferably, the compound of formula (2) is reacted with the compound of formula (3) in the presence of an organic solvent.
In one embodiment, the organic solvent is preferably a polar solvent, more preferably selected from any one of or any combination of water, methanol, ethanol, isopropanol, dimethylsulfoxide, N-dimethylformamide, N-dimethylacetamide or N-methylpyrrolidone, and even more preferably methanol/water.
In one embodiment, the amount of organic solvent used is 1 to 10mL relative to 1mmol of the compound of formula (2).
In one embodiment, the amount of the compound of formula (3) used is 1 to 10 equivalents with respect to 1 equivalent of the compound of formula (2).
According to the present invention, the reaction time is different for different compounds of formula (2) and different compounds of formula (3), and there is no particular limitation as long as the reaction can be completed. For example, the reaction time may be at least 1 hour, at least 2 hours, 12-48 hours, or 15-36 hours.
According to the present invention, the reaction temperature is different for different compounds of formula (2) and different compounds of formula (3), and there is no particular limitation as long as the reaction can be completed. For example, the reaction temperature may be 20 to 100 ℃, 30 to 70 ℃, 35 to 60 ℃ or 40 to 50 ℃.
In a third aspect, the present invention provides a compound of formula (6) or a salt thereof:
Figure BDA0002653547590000051
wherein R is10And R11The same or different, each independently selected from hydrogen and C1-C6Alkyl radical, C3-C8Cycloalkyl radical, C6-C20Aryl radical, C5-C20Heteroaryl group, C3-C18Heterocyclic group, C2-C6Alkenyl radical, C2-C6Alkynyl, above C1-C6Alkyl radical, C3-C8Cycloalkyl radical, C6-C20Aryl radical, C5-C20Heteroaryl group, C3-C18Heterocyclic group, C2-C6Alkenyl radical, C2-C6Alkynyl, optionally unsubstituted or substituted by one or moreEach substituent being independently selected from the group consisting of C1-C6Alkyl radical, C3-C8Cycloalkyl radical, C6-C20Aryl radical, C5-C20Heteroaryl group, C3-C18Heterocyclic group, C2-C6Alkenyl radical, C2-C6Alkynyl, amino, hydroxyl, mercapto, carboxyl, C1-C6Alkoxy radical, C3-C18Cycloalkoxy, C6-C20Halogenated aryl, C2-C6Alkoxycarbonyl, acyloxy, amido, ureido, C1-C6Alkylsulfonyl radical, C6-C20Arylsulfonyl radical, C1-C6Haloalkyl, F, Cl, Br, I, cyano, nitro, nitroso, thiocyano, isothiocyanato, C1-C6Sulfanyl, C1-C6Sulfoalkyl radical, C3-C8Cycloalkyl radical, C6-C20Aryl radical, C5-C20Heteroaryl group, C3-C18Heterocyclic group, C2-C6Alkenyl radical, C2-C6Alkynyl as a substituent alone or in free combination with the proviso that when R is10Or R11Any one of which is ethyl, butyl, trifluoroethyl,
Figure BDA0002653547590000061
Figure BDA0002653547590000062
When the other is not H; or R10And R11Together with the N atom to which they are attached, form a heterocyclic group which is monocyclic, bicyclic or tricyclic, or which is a fused, bridged or spirocyclic ring, which heterocyclic group contains only one N atom or optionally in addition to the above-mentioned N atoms 1 or 2 or 3 heteroatoms selected from N, S and O, which heterocyclic group is unsubstituted or optionally substituted by one or more substituents each independently selected from the group consisting of C1-C6Alkyl radical, C3-C8Cycloalkyl radical, C6-C20Aryl radical, C5-C20Heteroaryl group, C3-C18Heterocyclic group, C2-C6Alkenyl radical, C2-C6Alkynyl, amino, hydroxyl, mercapto, carboxyl, C1-C6Alkoxy radical, C3-C8Cycloalkoxy, C2-C6Alkoxycarbonyl, F, Cl, Br, I, cyano, nitro, nitroso, amido, thiocyano, isothiocyanato, ureido, sulfo, alone or in combination; z is H, C1-C6Alkyl radical, C1-C6Alkoxy, F, Cl, Br, I, CN, NO2、CF3Or C2-C6Ester group with the proviso that when R10And R11And when H is the same, Z is not CN; g1、G2、G3、G4、G5Is N or CR ', wherein R' is selected from H, C1-C6Alkyl radical, C1-C6Alkoxy, CN, CF3、C2-C6Ester group, NO2F, Cl, Br or I, and G1To G5At least one of which is not N; y is F, Cl, Br, I, C1-C6Alkyl radical, C1-C6Alkoxy, CN, NO2、CF3Amino or C2-C6An ester group, and n is 0, 1,2, 3 or 4.
Preferably, in the compound of formula (6), R10And R11Independently selected from hydrogen, C1-C6Alkyl radical, C3-C8Cycloalkyl radical, C6-C20Aryl radical, C5-C20Heteroaryl group, C3-C18Heterocyclic group, C2-C6Alkenyl radical, C2-C6Alkynyl, above C1-C6Alkyl radical, C3-C8Cycloalkyl radical, C6-C20Aryl radical, C5-C20Heteroaryl group, C3-C18Heterocyclic group, C2-C6Alkenyl radical, C2-C6Alkynyl, optionally unsubstituted or substituted with one or more substituents each independently selected from the group consisting of1-C6Alkyl radical, C3-C8Cycloalkyl radical, C6-C20Aryl radical, C5-C20Heteroaryl group, C3-C18Heterocyclic group, C2-C6Alkenyl radical, C2-C6Alkynyl, amino, hydroxyl, mercapto, carboxyl, C1-C6Alkoxy radical, C3-C18Cycloalkoxy, C2-C6Alkoxycarbonyl, acyloxy, amido, ureido, C1-C6Alkylsulfonyl radical, C6-C20Arylsulfonyl, F, Cl, Br, I, cyano, nitro, nitroso, thiocyano, isothiocyanato, C1-C6Sulfanyl, C3-C8Cycloalkyl radical, C6-C20Aryl radical, C5-C20Heteroaryl group, C3-C18Heterocyclic group, C2-C6Alkenyl radical, C2-C6Alkynyl as a substituent alone or in free combination with the proviso that when R is10Or R11Any one of them is C1-C4Alkyl radical, C1-C2Haloalkyl, C substituted by hydroxy1-C6Alkyl, or anthracenedione substituted with amino, 4-sulfonylfluoroaniline, the other is not H; or R10And R11Together with the N atom to which they are attached, form a heterocyclic group which is monocyclic, bicyclic or tricyclic, or which is a fused, bridged or spirocyclic ring, which heterocyclic group contains only one N atom or optionally in addition to the above-mentioned N atoms 1 or 2 or 3 heteroatoms selected from N, S and O, which heterocyclic group is unsubstituted or optionally substituted by one or more substituents each independently selected from the group consisting of C1-C6Alkyl radical, C3-C8Cycloalkyl radical, C6-C20Aryl radical, C5-C20Heteroaryl group, C3-C18Heterocyclic group, C2-C6Alkenyl radical, C2-C6Alkynyl, amino, hydroxyl, mercapto, carboxyl, C1-C6Alkoxy radical, C3-C8Cycloalkoxy, C2-C6Alkoxycarbonyl, F, Cl, Br, I, cyano, nitro, nitroso, amido, thiocyano, isothiocyanato, ureido, sulfo, alone or in combination; g1To G5At least two of which are not N.
Further preferably, the compound of formula (6) is selected from:
Figure BDA0002653547590000071
Figure BDA0002653547590000081
Figure BDA0002653547590000091
in a fourth aspect, the present invention provides a process for the preparation of a compound of formula (6), which comprises subjecting a compound of formula (4) to nucleophilic substitution or coupling reaction with a compound of formula (5) to give a compound of formula (6):
Figure BDA0002653547590000092
wherein X is F, Cl, Br or I, G1、G2、G3、G4、G5、Y、n、Z、R10And R11Is as defined in formula (6).
Preferably, the compound of formula (4) is reacted with the compound of formula (5) in the presence of an organic solvent and an acid.
In one embodiment, the organic solvent is preferably a polar solvent, more preferably selected from methanol, ethanol, isopropanol, dimethyl sulfoxide, N-dimethylformamide, N-dimethylacetamide or N-methylpyrrolidone.
In one embodiment, the organic solvent is used in an amount of 1 to 10mL with respect to 1mmol of the compound of formula (4).
In one embodiment, the acid is preferably concentrated hydrochloric acid, concentrated phosphoric acid, concentrated sulfuric acid or concentrated nitric acid, more preferably concentrated hydrochloric acid or concentrated phosphoric acid. In one embodiment, the acid is used in an amount of 1 to 10 equivalents with respect to 1 equivalent of the compound of formula (4).
In one embodiment, the compound of formula (5) is used in an amount of 1 to 10 equivalents with respect to 1 equivalent of the compound of formula (4).
According to the present invention, the reaction time is different for different compounds of formula (4) and different compounds of formula (5), and there is no particular limitation as long as the reaction can be completed. For example, the reaction time may be at least 1 hour, at least 2 hours, 9-48 hours, or 15-36 hours.
According to the present invention, the reaction temperature is different for different compounds of formula (4) and different compounds of formula (5), and there is no particular limitation as long as the reaction can be completed. For example, the reaction temperature may be 40-100 ℃, 50-90 ℃, 60-80 ℃ or 70 ℃.
In a fifth aspect, the present invention provides the use of a compound of formula (4) and a compound of formula (6) or a salt thereof in the preparation of a sulfonamide compound.
In a sixth aspect, the present invention provides a process for the preparation of a compound of formula (1), which comprises subjecting a compound of formula (6) and a compound of formula (7) to a nucleophilic substitution reaction to obtain a compound of formula (1), the reaction being carried out in the presence of a catalyst and optionally an additive or optionally a base:
Figure BDA0002653547590000101
wherein R is1And R2The same or different, each independently selected from hydrogen and C1-C6Alkyl radical, C3-C8Cycloalkyl radical, C6-C20Aryl radical, C5-C20Heteroaryl group, C3-C18Heterocyclic group, C2-C6Alkenyl radical, C2-C6Alkynyl, above C1-C6Alkyl radical, C3-C8Cycloalkyl radical, C6-C20Aryl radical, C5-C20Heteroaryl group, C3-C18Heterocyclic group, C2-C6Alkenyl radical, C2-C6Alkynyl, optionally unsubstituted or substituted with one or more substituents each independently selected from the group consisting of1-C6Alkyl radical, C3-C8Cycloalkyl radical, C6-C20Aryl radical, C5-C20Heteroaryl group, C3-C18Heterocyclic group, C2-C6Alkenyl radical, C2-C6Alkynyl, amino, hydroxyl, mercapto, carboxyl, C1-C6Alkoxy radical, C3-C18Cycloalkoxy, C6-C20Halogenated aryl, C2-C6Alkoxycarbonyl, acyloxy, amido, ureido, C1-C6Alkylsulfonyl radical, C6-C20Arylsulfonyl radical, C1-C6Haloalkyl, F, Cl, Br, I, cyano, nitro, nitroso, thiocyano, isothiocyanato, C1-C6Sulfanyl, C1-C6Sulfoalkyl radical, C3-C8Cycloalkyl radical, C6-C20Aryl radical, C5-C20Heteroaryl group, C3-C18Heterocyclic group, C2-C6Alkenyl radical, C2-C6Alkynyl is taken as a substituent independently or is formed by free combination; or R10And R11Together with the N atom to which they are attached, form a heterocyclic group which is monocyclic, bicyclic or tricyclic, or which is a fused, bridged or spirocyclic ring, which heterocyclic group contains only one N atom or optionally in addition to the above-mentioned N atoms 1 or 2 or 3 heteroatoms selected from N, S and O, which heterocyclic group is unsubstituted or optionally substituted by one or more substituents each independently selected from the group consisting of C1-C6Alkyl radical, C3-C8Cycloalkyl radical, C6-C20Aryl radical, C5-C20Heteroaryl group, C3-C18Heterocyclic group, C2-C6Alkenyl radical, C2-C6Alkynyl, amino, hydroxyl, mercapto, carboxyl, C1-C6Alkoxy radical, C3-C8Cycloalkoxy, C2-C6Alkoxycarbonyl, F, Cl, Br, I, cyano, nitro, nitroso, amido, thiocyano, isothiocyanato, ureido, sulfo, alone or in combination; g1、G2、G3、G4、G5、Y、n、Z、R10And R11Is as defined in formula (6).
In one embodiment, the catalyst is a compound of formula (I) or a compound of formula (II), or a combination thereof:
Figure BDA0002653547590000111
in the formulae (I) and (II), R1And R2Are each independently of the others selected from hydrogen, hydroxy, F, Cl, Br, I, C1-C6Alkyl radical, NO2、C1-C6Alkoxy, amino, C1-C6Alkyl monosubstituted amino, C1-C6Alkyl-disubstituted amino, C1-C6Haloalkyl, C1-C6An alkyloxycarbonyl group; or R1And R2Together with the carbon atom to which they are attached form ring a;
the ring A is selected from: a monocyclic or compensated bicyclic aromatic ring having 6-10 carbon atoms; a monocyclic or compensated bicyclic heteroaryl ring having 5-10 ring atoms comprising 1-3 heteroatoms selected from N, O, S and any combination thereof; a monocyclic or fused bicyclic carbocycle having 3-10 carbon atoms; a monocyclic or compensated bicyclic heterocycle having 3-10 ring atoms comprising 1-3 heteroatoms selected from N, O, S and any combination thereof;
said ring A being optionally substituted by one or more than one substituent RaSubstituted, each substituent RaIdentical or different, independently of one another, from the group consisting of hydroxyl, F, Cl, Br, I, C1-C18Alkyl radical, NO2、C1-C18Alkoxy, amino, C1-C6Alkyl monosubstituted amino, C1-C6Alkyl-disubstituted amino, C1-C6Haloalkyl, C1-C6Alkyl oxycarbonyl radical, C6-C10Aryl, benzyl;
R3are respectively selected from hydrogen, hydroxyl, sulfydryl, F, Cl, Br, I and C1-C6Alkyl radical, NO2、C1-C6Alkoxy, amino, C1-C6Alkyl monosubstituted amino, C1-C6Alkyl-disubstituted amino, C1-C6Haloalkyl, C1-C18Alkyloxycarbonyl, oxytris (pyrrolidinyl) phosphonium hexafluorophosphate, oxytris (pyrrolidinyl) phosphonium tetrafluoroborate, oxytris (dimethylamino) phosphonium hexafluorophosphate, oxytris (dimethylamino) phosphonium tetrafluoroborate, oxydi (dimethylamino) carbonium hexafluorophosphate, oxydi (dimethylamino) carbonium tetrafluoroborate, oxydi (pyrrolidinyl) carbonium hexafluorophosphate, oxydi (pyrrolidinyl) carbonium tetrafluoroborate, -OSO2C1-C6Alkyl, -OSO2C1-C8Perfluoroalkyl group, -OSO2C6-C10And (4) an aryl group.
According to the present invention, the activity of the catalyst is related to the substituents but is not particularly sensitive, so that the substituents are not particularly limited and can catalyze the reaction to some extent with respect to compounds having the same parent structure.
In one embodiment, the catalyst is selected from any one of the following compounds, or any combination thereof:
Figure BDA0002653547590000121
in a preferred embodiment, the catalyst is selected from
Figure BDA0002653547590000122
Or a combination thereof.
In one embodiment, the catalyst is used in an amount of 0.0001 to 2.0 equivalents with respect to 1 equivalent of the compound of formula (6).
In one embodiment, the additive is a silicon-containing compound selected from the group consisting of:
unsubstituted or substituted trimethylsilyl, C1-C4Alkyl radical, C1-C4Haloalkyl, phenyl, C1-C4Alkoxy or any combination thereof mono-or poly-substituted silane;
unsubstituted or by C1-C4Alkyl radical, C1-C4Haloalkyl, phenyl, C1-C4Alkoxy or any combination thereof mono-or poly-substituted disiloxane;
a compound of formula (III)
Figure BDA0002653547590000131
Wherein the substituent Re、Rf、Rg、Rh、Ri、Rj、RkIdentical or different, independently of one another, from hydrogen, C1-C4Alkyl radical, C1-C4Haloalkyl, phenyl, C1-C4An alkoxy group;
a compound of formula (IV)
Figure BDA0002653547590000132
Wherein R isl、Rm、Rn、Ro、Rp、RqIdentical or different, independently of one another, from hydrogen, C1-C4Alkyl radical, C1-C4Haloalkyl, phenyl, C1-C4An alkoxy group;
a compound of formula (V)
Figure BDA0002653547590000133
Wherein R isr、Rs、Rt、Ru、Rv、Rw、Rx、RyIdentical or different, independently of one another, from hydrogen, C1-C4Alkyl radical, C1-C4Haloalkyl, phenyl, C1-C4Alkoxy, n is 1-2000, preferably 10-1000, more preferably 100-500.
According to the present invention, the activity of the additive is related to the substituent but is not particularly sensitive as long as it satisfies the conditions of having a strong affinity for fluoride ions and being compatible with other substances in the reaction system, and the substituent is not particularly limited and can promote the reaction to some extent.
Preferably, the additive is selected from (TMS)2O, 1,1,3, 3-tetramethyldisiloxane, methyldiethoxysilane, silica gels, where n is 1-2000, preferably 10-1000, more preferably 100-500C3H9OSi·(CH4OSi)n·C3H9Si or any one or any combination of the following compounds:
Figure BDA0002653547590000141
in a preferred embodiment, the additive is selected from (TMS)2O, 1,3, 3-tetramethyldisiloxane, methyldiethoxysilane, or any combination thereof.
In one embodiment, the additive is used in an amount of 0 to 10 equivalents with respect to 1 equivalent of the compound of formula (6).
In one embodiment, the base is an organic or inorganic base selected from the group consisting of: r11R12NR13Wherein R is11、R12And R13Independently of one another, from hydrogen, C1-C4An alkyl group; r21R22N-Y-NR23R24Y is C1-C3Alkylene radical, R21、R22、R23And R24Independently of one another, from hydrogen, C1-C4An alkyl group; unsubstituted or substituted by halogen, C1-C4Alkyl-substituted diaza or triazabicyclo C6-C12An olefin;
Figure BDA0002653547590000142
Figure BDA0002653547590000151
Figure BDA0002653547590000152
wherein R is41、R42、R43、R44、R45Independently of one another, from hydrogen, C1-C4An alkyl group;
the inorganic base is selected from carbonates, phosphates, hydrides and C of alkali metals or alkaline earth metals1-C18An alkyl oxide;
preferably, the base is selected from triethylamine, diisopropyldiethylamine, 1, 8-diazabicyclo [5.4.0] undec-7-ene (DBU), 1,5, 7-triazabicyclo [4.4.0] dec-5-ene (TBD), 1, 4-diazabicyclo [2.2.2] octane (DABCO), potassium carbonate, cesium carbonate, potassium phosphate, 2-tert-butylimino-2-diethylamino-1, 3-dimethylperhydro-1, 3, 2-diazaphosphorus (BEMP) and 2-tert-butyl-1, 1,3, 3-tetramethylguanidine (Barton base);
more preferably, the base is triethylamine or diisopropylethylamine.
In one embodiment, the base is used in an amount of 0 to 10 equivalents with respect to 1 equivalent of the compound of formula (6).
In one embodiment, the compound of formula (7) is used in an amount of 0.2 to 10 equivalents with respect to 1 equivalent of the compound of formula (6).
The nucleophilic substitution reaction can be carried out in the presence or absence of a solvent. In the case of using a solvent, the solvent is an organic solvent, and the kind and amount of the organic solvent are not particularly limited as long as the reactants, the catalyst, and the optional additive or the optional base can be partially dissolved.
In one embodiment, the solvent is selected from C1-C4Alcohol solutionAgent, C1-C4Nitrile solvent, C1-C4Halogenated hydrocarbon solvent, C6-C10Aromatic hydrocarbon solvent, C2-C4Sulfone solvent and C3-C6An amide solvent; preferably, the solvent is selected from methanol, ethanol, isopropanol, tert-butanol, acetonitrile, dichloromethane, toluene, N-dimethylformamide, N-dimethylacetamide, dimethylsulfoxide or, N-methylpyrrolidone; more preferably, the solvent is dichloromethane, dimethyl sulfoxide, N-methylpyrrolidone or N, N-dimethylformamide. In one embodiment, the solvent is used in an amount of 1 to 10mL with respect to 1mmol of the compound of formula (6).
According to the present invention, the nucleophilic substitution reaction is carried out for different compounds of formula (6) and different nucleophiles at different reaction times, and there is no particular limitation as long as the reaction can be completed. For example, the reaction time may be at least 1 hour, at least 2 hours, 3 to 10 hours, or 3 to 7 hours.
According to the present invention, the nucleophilic substitution reaction is carried out for different compounds of formula (6) and different nucleophiles at different reaction temperatures, which are not particularly limited as long as the reaction can be completed. For example, the reaction temperature may be 20 to 100 ℃, 30 to 80 ℃, 30 to 50 ℃ or 30 to 40 ℃.
Compared with the prior art, the invention has the following advantages: the preparation method disclosed by the invention is simple and safe to operate, does not need special purification equipment, can obtain reagents and raw materials for reaction in a commercially available manner, is mild in reaction condition, environment-friendly, pollution-free, high in product yield, high in purity and few in byproducts, can quickly prepare different types of sulfamide, and provides a brand-new method for preparing series compounds in medicinal chemistry.
Detailed Description
The abbreviations used in the present invention are summarized in the following table:
TABLE 1
Figure BDA0002653547590000161
Definition of
The term "alkyl" as used herein refers to a group consisting of only carbon and hydrogen atoms, and having no unsaturation (e.g., double bonds, triple bonds, or rings), which encompasses a wide variety of possible geometric and stereoisomeric groups. This group is attached to the rest of the molecule by a single bond. By way of non-limiting examples of alkyl groups, mention may be made of the following linear or branched groups: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl and seven further isomers thereof, n-hexyl and sixteen further isomers thereof, n-heptyl and respective isomers thereof, n-octyl and respective isomers thereof, n-nonyl and respective isomers thereof.
The term "cycloalkyl" as used herein refers to a saturated non-aromatic ring system of at least 3 carbon atoms which may be monocyclic, bicyclic, polycyclic, fused, bridged, or spiro. As non-limiting examples of cycloalkyl groups, the following groups may be cited: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl; and fused, bridged, or spiro ring groups formed from two or more of the above-described monocyclic rings via a common side and a common carbon atom.
The term "alkenyl" as used herein refers to a group formed in the presence of one or more double bonds (other than methyl) in the above alkyl group.
The term "alkynyl" as used herein refers to a group formed when one or more triple bonds (other than methyl) are present in the alkyl group described above.
The term "alkoxy" as used herein refers to a group having an oxygen atom attached to the alkyl group and a single bond through the oxygen atom to the rest of the molecule, and encompasses a wide variety of possible geometric and stereoisomeric groups. As non-limiting examples of alkoxy radicals, the following straight-chain or branched radicals may be cited: methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, n-pentoxy and further seven isomers, n-hexoxy and further sixteen isomers, n-heptoxy and various isomers, n-octoxy and various isomers, n-nonoxy and various isomers.
The term "aryl" as used herein refers to an aromatic ring system consisting of at least 6 carbon atoms, which may be monocyclic, bicyclic, polycyclic, wherein bicyclic and polycyclic rings may be formed from a single ring by single bond linkages or by fusion. As non-limiting examples of aryl groups, the following groups may be cited: phenyl, naphthyl, anthryl, phenanthryl, indenyl, pyrenyl, perylenyl, pentalenyl, heptalenyl, triphenylenyl, tetracenyl, pentalenyl, pentacenyl, tetrao-phenylene, hexaphenyl, hexacenyl, coronenyl, trinaphthyl, heptenyl, heptaphenyl, egg phenyl, biphenyl, binaphthyl.
The term "heteroaryl" as used herein refers to a 5-20 membered aromatic heterocyclic ring system having one or more heteroatoms independently selected from N, O or S, which may be monocyclic, bicyclic, polycyclic, wherein bicyclic and polycyclic rings may be formed from a single ring by single bond linkages or fused. As non-limiting examples of heteroaryl groups, the following groups may be cited: oxazolyl, isoxazolyl, imidazolyl, furyl, indolyl, isoindolyl, pyrrolyl, triazolyl, triazinyl, tetrazolyl, thienyl, thiazolyl, isothiazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzofuryl, benzothiazolyl, benzoxazolyl, benzimidazolyl, benzothienyl, benzofuryl, carbazolyl, isoquinolyl, quinazolinyl, naphthyridinyl, purinyl, thiadiazolyl, indolizinyl, phenazinyl, coumarinyl, pyridopyridyl, pyridopyridazinyl, imidazopyridyl, imidazopyridazinyl; and a group formed by the above-mentioned heteroaryl group by a single bond connection or a fusion connection.
The term "heterocyclyl" as used herein, means a non-aromatic 3-18 membered ring system consisting of carbon atoms and heteroatoms independently selected from N, O or S, which ring system may be monocyclic, bicyclic, or polycyclic, and may be fused, bridged, or spiro, and may optionally contain one or more double bonds. As non-limiting examples of heterocyclyl groups, the following groups may be mentioned: acridinyl, benzodioxacyclohexyl, benzopyranyl, chromanyl, dioxolanyl, decahydroisoquinolinyl, indanyl, indolinyl, isoindolinyl, isochromanyl, morpholinyl, piperazinyl, 2-oxopiperazinyl, octahydroindolyl, octahydroisoindolyl, 4-piperidinonyl, dihydroquinolinyl, dihydroisoquinolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, 1- (diphenylmethyl) piperazinyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, and combinations thereof.
The salt of the compound of formula (4) or the salt of the compound of formula (6) means a pharmaceutically acceptable salt and ordinary salts thereof, for example, a base addition salt with a carboxyl group when the compound has a carboxyl group, an acid addition salt with an amino group or a basic heterocyclic group when the compound has an amino group or a basic heterocyclic group, and the like.
The above base addition salts include those with alkali metals (e.g., sodium, potassium); alkaline earth metals (e.g., calcium, magnesium); ammonium or organic amines (e.g., trimethylamine, triethylamine, dicyclohexylamine, ethanolamine), and the like.
The above-mentioned acid addition salts include salts with inorganic acids (e.g., hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, perchloric acid), organic acids (e.g., maleic acid, fumaric acid, tartaric acid, citric acid, ascorbic acid, trifluoroacetic acid), sulfonic acids (methanesulfonic acid, isethionic acid, phenylmethanesulfonic acid, p-toluenesulfonic acid), and the like.
In the present invention, a numerical range covers any number within the range.
Reagents used in the present invention are commercially available unless otherwise specifically indicated.
Examples
The present invention is further illustrated by the following examples, but the present invention is not limited to these specific examples, and may be arbitrarily changed without departing from the spirit and scope of the present invention.
EXAMPLE 1 Synthesis of a Compound of formula 4 (3- (2-chloro-5-methylpyrimidin-4-amino) benzenesulfonyl fluoride)
Figure BDA0002653547590000191
To a reaction flask was added 3-aminobenzenesulfonyl fluoride (1.80g, 10.3mmol), 2, 4-dichloro-5-methylpyrimidine (2.00g, 1.2eq), methanol/water ═ 1:1(34mL), and the reaction was carried out at 45 ℃ for 24 hours. White solid is separated out in the reaction process, the reaction product is filtered, a filter cake is washed by methanol/water (1: 1), and the filter cake is dried to obtain the white solid with the yield of 88%. The detection result is as follows: ms (esi): 302.0(35Cl)，303.9(37Cl)[M+H]+。
Example 2 Synthesis of Compound of formula 4 (3- ((2-Chloropyrimidin-4-yl) amino) benzenesulfonyl fluoride)
Figure BDA0002653547590000192
To a reaction flask were added 3-aminobenzenesulfonyl fluoride (35.0mg, 0.2mmol), 2, 4-dichloropyrimidine (35.8mg, 1.2eq), methanol/water ═ 1:1(0.66mL), and the mixture was reacted at 45 ℃ for 24 hours. The detection result is as follows: ms (esi): 286.0(35Cl)，288.0(37Cl)[M-H]-。
EXAMPLE 3 Synthesis of Compound of formula 4 (3- ((2-chloro-5-fluoropyrimidin-4-yl) amino) benzenesulfonyl fluoride)
Figure BDA0002653547590000193
To a reaction flask were added 3-aminobenzenesulfonyl fluoride (35.0mg, 0.2mmol), 2, 4-dichloro-5-fluoropyrimidine (40.0mg, 1.2eq), methanol/water ═ 1:1(0.66mL), and reacted at 45 ℃ for 24 hours. The detection result is as follows: ms (esi): 304.0(35Cl)，305.9(37Cl)[M-H]-。
EXAMPLE 4 Synthesis of Compound of formula 4 (3- ((2-chloro-5-nitropyrimidin-4-yl) amino) benzenesulfonyl fluoride)
Figure BDA0002653547590000201
Adding 3-aminobenzenesulfonic acid into a reaction bottleAcyl fluoride (35.0mg, 0.2mmol), 2, 4-dichloro-5-nitropyrimidine (46.6mg, 1.2eq), methanol/water ═ 1:1(0.66mL), and reacted at 45 ℃ for 24 hours. The detection result is as follows: ms (esi): 330.9(35Cl)，332.9(37Cl)[M-H]-。
EXAMPLE 5 Synthesis of Compound of formula 4 (3- ((2-chloro-5-trifluoromethylpyrimidin-4-yl) amino) benzenesulfonyl fluoride)
Figure BDA0002653547590000202
To a reaction flask was added 3-aminobenzenesulfonyl fluoride (35.0mg, 0.2mmol), 2, 4-dichloro-5-trifluoromethylpyrimidine (52.1mg, 1.2eq), methanol/water ═ 1:1(0.66mL), and reacted at 45 ℃ for 24 hours. The detection result is as follows: ms (esi): 353.9(35Cl)，355.9(37Cl)[M-H]-。
EXAMPLE 6 Synthesis of Compound of formula 4 (ethyl 2-chloro-4- ((3- (fluorosulfonyl) phenyl) amino) pyrimidine-5-carboxylate)
Figure BDA0002653547590000203
To a reaction flask were added 3-aminobenzenesulfonyl fluoride (35.0mg, 0.2mmol), ethyl 2, 4-dichloro-5-pyrimidinecarboxylate (53.0mg, 1.2eq), methanol/water ═ 1:1(0.66mL), and reacted at 45 ℃ for 24 hours. The detection result is as follows: ms (esi): 357.9(35Cl)，359.9(37Cl)[M-H]-。
EXAMPLE 7 Synthesis of Compound of formula 4 (3- ((6-chloro-5-cyano-4-methylpyridin-2-yl) amino) benzenesulfonyl fluoride)
Figure BDA0002653547590000211
To a reaction flask was added 3-aminobenzenesulfonyl fluoride (35.0mg, 0.2mmol), 3-cyano-4-methyl-2, 6-dichloropyridine (44.9mg, 1.2eq), methanol/water ═ 1:1(0.66mL), and the reaction was carried out at 45 ℃ for 24 hours. The detection result is as follows: ms (esi): 324.0(35Cl)，326.0(37Cl)[M-H]-。
EXAMPLE 8 Synthesis of Compound of formula 4 (3- ((6-chloro-5-nitropyridin-3-yl) amino) benzenesulfonyl fluoride)
Figure BDA0002653547590000212
To a reaction flask were added 3-aminobenzenesulfonyl fluoride (35.0mg, 0.2mmol), 2, 5-dichloro-3-nitropyridine (46.3mg, 1.2eq), methanol/water ═ 1:1(0.66mL), and the reaction was carried out at 45 ℃ for 24 hours. The detection result is as follows: ms (esi): 329.9(35Cl)，331.9(37Cl)[M-H]-。
Example 9 Synthesis of Compound of formula 4 (3- ((6-chloro-5- (trifluoromethyl) pyridin-2-yl) amino) benzenesulfonyl fluoride)
Figure BDA0002653547590000213
To a reaction flask was added 3-aminobenzenesulfonyl fluoride (35.0mg, 0.2mmol), 2, 6-dichloro-3-trifluoromethylpyridine (51.8mg, 1.2eq), isopropanol/water ═ 1:1(0.66mL), and reacted at 85 ℃ for 24 hours. The detection result is as follows: ms (esi): 352.9(35Cl)，354.9(37Cl)[M-H]-。
EXAMPLE 10 Synthesis of a Compound of formula 4 (3- ((2,3, 5-trichloro-4, 6-dicyanophenyl) amino) benzenesulfonyl fluoride)
Figure BDA0002653547590000221
3-Aminobenzenesulfonyl fluoride (35.0mg, 0.2mmol), tetrachloroisophthalonitrile (63.8mg, 1.2eq), and DMSO (1mL) were added to the reaction flask and reacted at 85 ℃ for 24 hours. The detection result is as follows: ms (esi): 401.8(335Cl)，403.8(2 35Cl+37Cl)[M-H]-。
EXAMPLE 11 Synthesis of the Compound of formula 6 (3- (2- (4- (2- (pyrrolidinyl-1-yl) ethoxy) phenylamino) -5-methylpyrimidin-4-ylamino) benzenesulfonyl fluoride)
Figure BDA0002653547590000222
3- (2-chloro-5-methylpyrimidin-4-amino) benzenesulfonyl fluoride (1.10g, 3.6mmol), 4- (2-pyrrolidin-1-yl-ethoxy) -phenylamine (1.00g, 1.3eq), 14mL isopropanol were added to the reaction flask. Adding 2.0eq concentrated hydrochloric acid, reacting at 70 ℃ for 24 hours, starting monitoring, cooling to room temperature after the reaction is finished, performing suction filtration, washing with 10mL isopropanol, and drying to obtain an off-white solid with the yield of 95%. The detection result is as follows: ms (esi): 472.1[ M + H]+。
EXAMPLE 12 Synthesis of a Compound of formula 6 (3- (2- (4- (2- (pyrrolidinyl-1-yl) ethoxy) phenylamino) -5-methylpyrimidin-4-ylamino) benzenesulfonyl fluoride)
Figure BDA0002653547590000223
3- (2-chloro-5-methylpyrimidin-4-amino) benzenesulfonyl fluoride (100.0mg, 0.33mmol), 4- (2-pyrrolidin-1-yl-ethoxy) -phenylamine (88.0mg, 1.3eq), 1.2mL of dimethylsulfoxide was added to the reaction flask. 1.4eq of concentrated HCl was added and the reaction was carried out at 70 ℃ for 24 hours. HPLC purity of crude product: 97 percent.
EXAMPLE 13 Synthesis of a Compound of formula 6 (3- ((2- ((4-methoxyphenyl) amino) -5-methylpyrimidin-4-yl) amino) benzenesulfonyl fluoride)
Figure BDA0002653547590000231
3- (2-chloro-5-methylpyrimidin-4-amino) benzenesulfonyl fluoride (30.2mg, 0.1mmol), p-anisidine (16.0mg, 1.3eq), 0.4mL of isopropanol were added to the reaction flask. 2.0eq of concentrated HCl was added and the reaction was carried out at 70 ℃ for 24 hours. The detection result is as follows: ms (esi): 387.0[ M-H ]]-。
EXAMPLE 14 Synthesis of Compound of formula 6 (3- ((2- ((4-fluorophenyl) amino) -5-methylpyrimidin-4-yl) amino) benzenesulfonyl fluoride)
Figure BDA0002653547590000232
3- (2-chloro-5-methylpyrimidin-4-amino) benzenesulfonyl fluoride (30.2mg, 0.1mmol), p-fluoroaniline (14.0mg, 1.3eq), 0.4mL isopropanol were added to the reaction flask. 2.0eq of concentrated HCl was added and the reaction was carried out at 70 ℃ for 24 hours. The detection result is as follows: ms (esi): 375.0[ M-H ]]-。
EXAMPLE 15 Synthesis of Compound of formula 6 ((S) -3- ((2- (((1- (4-chlorophenyl) ethyl) amino) -5-methylpyrimidin-4-yl) amino) benzenesulfonyl fluoride)
Figure BDA0002653547590000233
3- (2-chloro-5-methylpyrimidin-4-amino) benzenesulfonyl fluoride (30.2mg, 0.1mmol), S-4-chlorophenylethylamine (20.3mg, 1.3eq), 0.4mL of isopropanol were added to the reaction flask. 2.0eq of concentrated HCl was added and the reaction was carried out at 70 ℃ for 24 hours. The detection result is as follows: ms (esi): 421.0(35Cl)，422.9(37Cl)[M+H]+。
EXAMPLE 16 Synthesis of Compound of formula 6 (3- ((5-methyl-2- (pyridin-3-ylamino) pyrimidin-4-yl) amino) benzenesulfonyl fluoride)
Figure BDA0002653547590000241
3- (2-chloro-5-methylpyrimidin-4-amino) benzenesulfonyl fluoride (30.2mg, 0.1mmol), 3-aminopyridine (12.2mg, 1.3eq), 0.4mL isopropanol were added to the reaction flask. 2.0eq of concentrated HCl was added and the reaction was carried out at 70 ℃ for 24 hours. The detection result is as follows: ms (esi): 358.0[ M-H]-。
EXAMPLE 17 Synthesis of a Compound of formula 6 (3- ((5-methyl-2-morpholinopyrimidin-4-yl) amino) benzenesulfonyl fluoride)
Figure BDA0002653547590000242
3- (2-chloro-5-methylpyrimidin-4-amino) benzenesulfonyl fluoride (30.2mg, 0.1mmol), morpholine (11.0. mu.L, 1.3eq), 0.4mL of isofluranePropanol was added to the reaction flask. 2.0eq of concentrated HCl was added and the reaction was carried out at 70 ℃ for 24 hours. The detection result is as follows: ms (esi): 351.0[ M-H ]]-。
EXAMPLE 18 Synthesis of Compound of formula 6 (3- ((2- (((3s,5s,7s) -adamantan-1-yl) amino) -5-methylpyrimidin-4-yl) amino) benzenesulfonyl fluoride)
Figure BDA0002653547590000243
3- (2-chloro-5-methylpyrimidin-4-amino) benzenesulfonyl fluoride (30.2mg, 0.1mmol), 1-adamantanamine (19.7mg, 1.3eq), 0.4mL isopropanol were added to the reaction flask. 2.0eq of concentrated HCl was added and the reaction was carried out at 70 ℃ for 24 hours. The detection result is as follows: ms (esi): 417.1[ M + H]+。
EXAMPLE 19 Synthesis of Compound of formula 6 (3- ((2- (((1R,2R) -2-amino-1, 2-diphenylethyl) amino) -5-methylpyrimidin-4-yl) amino) benzenesulfonyl fluoride)
Figure BDA0002653547590000251
3- (2-chloro-5-methylpyrimidin-4-amino) benzenesulfonyl fluoride (30.2mg, 0.1mmol), R, R-diphenylethylenediamine (27.6mg, 1.3eq), 0.4mL of isopropanol were added to the reaction flask. 2.0eq of concentrated HCl was added and the reaction was carried out at 70 ℃ for 24 hours. The detection result is as follows: ms (esi): 478.0[ M + H]+。
EXAMPLE 20 Synthesis of a Compound of formula 6 (3- ((2- (dipropylamino) -5-methylpyrimidin-4-yl) amino) benzenesulfonyl fluoride)
Figure BDA0002653547590000252
3- (2-chloro-5-methylpyrimidin-4-amino) benzenesulfonyl fluoride (30.2mg, 0.1mmol), di-n-propylamine (17.8. mu.L, 1.3eq), 0.4mL of isopropanol were added to the reaction flask. 2.0eq of concentrated HCl was added and the reaction was carried out at 70 ℃ for 24 hours. The detection result is as follows: ms (esi): 367.1[ M + H]+。
EXAMPLE 21 Synthesis of a Compound of formula 6 (3- ((2- (dipropylamino) -5-methylpyrimidin-4-yl) amino) benzenesulfonyl fluoride)
Figure BDA0002653547590000253
3- (2-chloro-5-methylpyrimidin-4-amino) benzenesulfonyl fluoride (30.2mg, 0.1mmol), 3-aminobenzylamine (15.9mg, 1.3eq), 0.4mL of isopropanol were added to the reaction flask. 2.0eq of concentrated HCl was added and the reaction was carried out at 70 ℃ for 24 hours. The detection result is as follows: ms (esi): 386.0[ M-H ]]-。
EXAMPLE 22 Synthesis of Compound of formula 6 (3- ((5-methyl-2- ((2-phenylpropan-2-yl) amino) pyrimidin-4-yl) amino) benzenesulfonyl fluoride)
Figure BDA0002653547590000261
3- (2-chloro-5-methylpyrimidin-4-amino) benzenesulfonyl fluoride (30.2mg, 0.1mmol), α, α -dimethylbenzylamine (17.6mg, 1.3eq), 0.4mL of isopropanol were added to the reaction flask. 2.0eq of concentrated HCl was added and the reaction was carried out at 70 ℃ for 24 hours. The detection result is as follows: ms (esi): 401.1[ M + H]+。
EXAMPLE 23 Synthesis of Compound of formula 1 (N-tert-butyl-3- ((5-methyl-2- ((4- (2-pyrrolidin-1-ylethoxy) phenyl) amino) pyrimidin-4-yl) amino) benzenesulfonamide)
Figure BDA0002653547590000262
To a reaction flask was added the compound of formula 6 (3- (2- (4- (2- (pyrrolidinyl-1-yl) ethoxy) phenylamino) -5-methylpyrimidin-4-ylamino) benzenesulfonyl fluoride) (0.12mmol, 1.2eq), 125. mu.L DMSO, 2.0eq N, N-diisopropylethylamine, tert-butylamine (10.5. mu.L, 1.0eq), 0.2eq HOBt, 2.0eq (TMS)2O, reacting at 60 ℃ for 24 hours. The nuclear magnetic calculation yield is 89%.
EXAMPLE 24 Synthesis of Compound of formula 1 (N-tert-butyl-3- ((5-methyl-2- ((4- (2-pyrrolidin-1-ylethoxy) phenyl) amino) pyrimidin-4-yl) amino) benzenesulfonamide)
Figure BDA0002653547590000263
A reaction flask was charged with the compound of formula 6 (3- (2- (4- (2- (pyrrolidinyl-1-yl) ethoxy) phenylamino) -5-methylpyrimidin-4-ylamino) benzenesulfonyl fluoride) (0.24mmol, 1.2eq), 250. mu.L of DMSO, tert-butylamine (21.0. mu.L, 0.2mmol, 1.0eq), 0.01eq of HOBt, 2.0eq of N, N-diisopropylethylamine, 2.0eq 1,1,3, 3-tetramethyldisiloxane), reacted at 25 ℃ for 24 hours, and after the reaction was completed, 70mL of chloroform was added, washed twice with water, dried over anhydrous sodium sulfate, concentrated to dryness to give an off-white solid in an isolated yield of 93%.
EXAMPLE 25 Synthesis of Compound of formula 1 (N-tert-butyl-3- ((5-methyl-2- ((4- (2-pyrrolidin-1-ylethoxy) phenyl) amino) pyrimidin-4-yl) amino) benzenesulfonamide)
The reaction was carried out in the same manner as in example 25 except that the temperature was increased to 60 ℃, and the nuclear magnetic calculated yield was 100%.
EXAMPLE 26 Synthesis of Compound of formula 1 (N-tert-butyl-3- ((5-methyl-2- ((4- (2-pyrrolidin-1-ylethoxy) phenyl) amino) pyrimidin-4-yl) amino) benzenesulfonamide)
The reaction was carried out in the same manner as in example 25 except that the amount of HOBt was changed to 0.001eq and the temperature was increased to 60 ℃, whereby the nuclear magnetic calculation yield was 100%.
EXAMPLE 27 Synthesis of Compound of formula 1 (N-tert-butyl-3- ((5-methyl-2- ((4- (2-pyrrolidin-1-ylethoxy) phenyl) amino) pyrimidin-4-yl) amino) benzenesulfonamide)
The reaction was carried out in the same manner as in example 25 except that HOBt was replaced with Cl-HOBt, and the nuclear magnetic calculation yield was 92%.
EXAMPLE 28 Synthesis of Compound of formula 1 (N-tert-butyl-3- ((5-methyl-2- ((4- (2-pyrrolidin-1-ylethoxy) phenyl) amino) pyrimidin-4-yl) amino) benzenesulfonamide)
Except for replacing 1,1,3, 3-tetramethyldisiloxane by methyldiethoxysilane, the reaction was carried out in the same manner as in example 25, and the nuclear magnetic computation yield was 96%.
EXAMPLE 29 Synthesis of the Compound of formula 1 (N- ((3s,5s,7s) -adamantan-1-yl) -3- ((5-methyl-2- ((4- (2- (pyrrolidinyl-1-yl) ethoxy) phenyl) amino) pyrimidin-4-yl) amino) benzenesulfonamide)
Figure BDA0002653547590000271
A reaction flask was charged with the compound of formula 6 (3- (2- (4- (2- (pyrrolidinyl-1-yl) ethoxy) phenylamino) -5-methylpyrimidin-4-ylamino) benzenesulfonyl fluoride) (0.12mmol, 1.2eq), 125. mu.L of DMSO, 1-amantadine (15.1mg, 1.0eq), 0.01eq of HOBt, 2.0eq of N, N-diisopropylethylamine, 2.0eq of 1,1,3, 3-tetramethyldisiloxane and reacted at 25 ℃ for 24 hours. The detection result is as follows: ms (esi): 601.1[ M-H]-。
EXAMPLE 30 Synthesis of a Compound of formula 1 (3- ((5-methyl-2- ((4- (2- (pyrrolidinyl-1-yl) ethoxy) phenyl) amino) pyrimidin-4-yl) amino) -N- (2-phenylpropan-2-yl) benzenesulfonamide)
Figure BDA0002653547590000281
A reaction flask was charged with the compound of formula 6 (3- (2- (4- (2- (pyrrolidinyl-1-yl) ethoxy) phenylamino) -5-methylpyrimidin-4-ylamino) benzenesulfonyl fluoride) (0.12mmol, 1.2eq), 125. mu.L of DMSO, α, α -dimethylbenzylamine (13.5mg, 1.0eq), 0.01eq of HOBt, 2.0eq of N, N-diisopropylethylamine, 2.0eq of 1,1,3, 3-tetramethyldisiloxane, and reacted at 25 ℃ for 24 hours. The detection result is as follows: ms (esi): 585.1[ M-H]-。
EXAMPLE 31 Synthesis of Compound of formula 1 ((S) -3- ((5-methyl-2- ((4- (2- (pyrrolidinyl-1-yl) ethoxy) phenyl) amino) pyrimidin-4-yl) amino) -N- (1-phenylethyl) benzenesulfonamide)
Figure BDA0002653547590000282
To a reaction flask was added the compound of formula 6 (3- (2- (4- (2- (pyrrolidinyl-1-yl) ethoxy) phenylamino) -5-methylpyrimidin-4-ylamino) benzeneSulfonyl fluoride) (0.12mmol, 1.2eq), 125. mu.L of DMSO, S-phenethylamine (13.0. mu.L, 1.0eq), 0.01eq HOBt, 2.0eq N, N-diisopropylethylamine, 2.0eq 1,1,3, 3-tetramethyldisiloxane, reacted at 25 ℃ for 24 hours. The detection result is as follows: ms (esi): 571.1[ M-H]-。

Claims (10)

1. A compound of formula (4) or a salt thereof:
Figure FDA0002653547580000011
wherein X is F, Cl, Br or I, Z is H, C1-C10Alkyl radical, C1-C10Alkoxy, F, Cl, Br, I, CN, NO2、CF3Or C2-C10Ester group, G1、G2、G3、G4、G5Is N or CR ', wherein R' is selected from H, C1-C10Alkyl radical, C1-C10Alkoxy, CN, CF3、C2-C10Ester group, NO2F, Cl, Br or I, and G1To G5At least one of which is not N; y is F, Cl, Br, I, C1-C10Alkyl radical, C1-C10Alkoxy, CN, NO2、CF3Amino or C2-C10An ester group, and n is 0, 1,2, 3 or 4.
2. The compound of formula (4) according to claim 1, X is F, Cl or Br, Z is H, C1-C6Alkyl radical, C1-C6Alkoxy, F, Cl, Br, I, CN, NO2、CF3Or C2-C6Ester group, G1、G2、G3、G4、G5Is N or CR ', wherein R' is selected from H, C1-C6Alkyl radical, C1-C6Alkoxy, CN, CF3、C2-C6Ester group, NO2F, Cl, Br or I, and G1To G5At least two of which are not N; y is F, Cl、Br、I、C1-C6Alkyl radical, C1-C6Alkoxy, CN, NO2、CF3Amino or C2-C6An ester group, and n is 0, 1,2, 3 or 4.
3. The compound of formula (4) according to claim 1 or 2, wherein the compound of formula (4) is selected from:
Figure FDA0002653547580000012
Figure FDA0002653547580000021
4. a process for the preparation of a compound of formula (4), which comprises reacting a compound of formula (2) with a compound of formula (3) via nucleophilic substitution or coupling to give a compound of formula (4):
Figure FDA0002653547580000031
wherein, X, Z, G1、G2、G3、G4、G5Y and n are as defined in claim 1;
preferably, the compound of formula (2) is reacted with the compound of formula (3) in the presence of an organic solvent; the organic solvent is preferably a polar solvent, more preferably any one selected from water, methanol, ethanol, isopropanol, dimethyl sulfoxide, N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone, or any combination thereof;
the amount of the solvent is 1-10mL relative to 1mmol of the compound of formula (2);
the compound of formula (3) is used in an amount of 1 to 10 equivalents with respect to 1 equivalent of the compound of formula (2).
5. A compound of formula (6) or a salt thereof:
Figure FDA0002653547580000032
wherein R is10And R11The same or different, each independently selected from hydrogen and C1-C6Alkyl radical, C3-C8Cycloalkyl radical, C6-C20Aryl radical, C5-C20Heteroaryl group, C3-C18Heterocyclic group, C2-C6Alkenyl radical, C2-C6Alkynyl, above C1-C6Alkyl radical, C3-C8Cycloalkyl radical, C6-C20Aryl radical, C5-C20Heteroaryl group, C3-C18Heterocyclic group, C2-C6Alkenyl radical, C2-C6Alkynyl, optionally unsubstituted or substituted with one or more substituents each independently selected from the group consisting of1-C6Alkyl radical, C3-C8Cycloalkyl radical, C6-C20Aryl radical, C5-C20Heteroaryl group, C3-C18Heterocyclic group, C2-C6Alkenyl radical, C2-C6Alkynyl, amino, hydroxyl, mercapto, carboxyl, C1-C6Alkoxy radical, C3-C18Cycloalkoxy, C6-C20Halogenated aryl, C2-C6Alkoxycarbonyl, acyloxy, amido, ureido, C1-C6Alkylsulfonyl radical, C6-C20Arylsulfonyl radical, C1-C6Haloalkyl, F, Cl, Br, I, cyano, nitro, nitroso, thiocyano, isothiocyanato, C1-C6Sulfanyl, C1-C6Sulfoalkyl radical, C3-C8Cycloalkyl radical, C6-C20Aryl radical, C5-C20Heteroaryl group, C3-C18Heterocyclic group, C2-C6Alkenyl radical, C2-C6Alkynyl as a substituent alone or in free combinationProvided that when R is10Or R11Any one of which is ethyl, butyl, trifluoroethyl,
Figure FDA0002653547580000041
Figure FDA0002653547580000042
When the other is not H; or R10And R11Together with the N atom to which they are attached, form a heterocyclic group which is monocyclic, bicyclic or tricyclic, or which is a fused, bridged or spirocyclic ring, which heterocyclic group contains only one N atom or optionally in addition to the above-mentioned N atoms 1 or 2 or 3 heteroatoms selected from N, S and O, which heterocyclic group is unsubstituted or optionally substituted by one or more substituents each independently selected from the group consisting of C1-C6Alkyl radical, C3-C8Cycloalkyl radical, C6-C20Aryl radical, C5-C20Heteroaryl group, C3-C18Heterocyclic group, C2-C6Alkenyl radical, C2-C6Alkynyl, amino, hydroxyl, mercapto, carboxyl, C1-C6Alkoxy radical, C3-C8Cycloalkoxy, C2-C6Alkoxycarbonyl, F, Cl, Br, I, cyano, nitro, nitroso, amido, thiocyano, isothiocyanato, ureido, sulfo, alone or in combination; z is H, C1-C6Alkyl radical, C1-C6Alkoxy, F, Cl, Br, I, CN, NO2、CF3Or C2-C6Ester group with the proviso that when R10And R11And when H is the same, Z is not CN; g1、G2、G3、G4、G5Is N or CR ', wherein R' is selected from H, C1-C6Alkyl radical, C1-C6Alkoxy, CN, CF3、C2-C6Ester group, NO2F, Cl, Br or I, and G1To G5At least one of which is not N; y is F, Cl, Br, I,C1-C6Alkyl radical, C1-C6Alkoxy, CN, NO2、CF3Amino or C2-C6An ester group, and n is 0, 1,2, 3 or 4.
6. A compound of formula (6) according to claim 5, wherein R10And R11Independently selected from hydrogen, C1-C6Alkyl radical, C3-C8Cycloalkyl radical, C6-C20Aryl radical, C5-C20Heteroaryl group, C3-C18Heterocyclic group, C2-C6Alkenyl radical, C2-C6Alkynyl, above C1-C6Alkyl radical, C3-C8Cycloalkyl radical, C6-C20Aryl radical, C5-C20Heteroaryl group, C3-C18Heterocyclic group, C2-C6Alkenyl radical, C2-C6Alkynyl, optionally unsubstituted or substituted with one or more substituents each independently selected from the group consisting of1-C6Alkyl radical, C3-C8Cycloalkyl radical, C6-C20Aryl radical, C5-C20Heteroaryl group, C3-C18Heterocyclic group, C2-C6Alkenyl radical, C2-C6Alkynyl, amino, hydroxyl, mercapto, carboxyl, C1-C6Alkoxy radical, C3-C18Cycloalkoxy, C2-C6Alkoxycarbonyl, acyloxy, amido, ureido, C1-C6Alkylsulfonyl radical, C6-C20Arylsulfonyl, F, Cl, Br, I, cyano, nitro, nitroso, thiocyano, isothiocyanato, C1-C6Sulfanyl, C3-C8Cycloalkyl radical, C6-C20Aryl radical, C5-C20Heteroaryl group, C3-C18Heterocyclic group, C2-C6Alkenyl radical, C2-C6Alkynyl is taken as a substituent independently or is formed by free combination; with the proviso that when R10Or R11Any one of them is C1-C4Alkyl radical, C1-C2Haloalkyl, C substituted by hydroxy1-C6Alkyl, or anthracenedione substituted with amino, 4-sulfonylfluoroaniline, the other is not H; or R10And R11Together with the N atom to which they are attached, form a heterocyclic group which is monocyclic, bicyclic or tricyclic, or which is a fused, bridged or spirocyclic ring, which heterocyclic group contains only one N atom or optionally in addition to the above-mentioned N atoms 1 or 2 or 3 heteroatoms selected from N, S and O, which heterocyclic group is unsubstituted or optionally substituted by one or more substituents each independently selected from the group consisting of C1-C6Alkyl radical, C3-C8Cycloalkyl radical, C6-C20Aryl radical, C5-C20Heteroaryl group, C3-C18Heterocyclic group, C2-C6Alkenyl radical, C2-C6Alkynyl, amino, hydroxyl, mercapto, carboxyl, C1-C6Alkoxy radical, C3-C8Cycloalkoxy, C2-C6Alkoxycarbonyl, F, Cl, Br, I, cyano, nitro, nitroso, amido, thiocyano, isothiocyanato, ureido, sulfo, alone or in combination; g1To G5At least two of which are not N.
7. The compound of formula (6) according to claim 5 or 6, wherein the compound of formula (6) is selected from:
Figure FDA0002653547580000051
Figure FDA0002653547580000061
Figure FDA0002653547580000071
8. a process for the preparation of a compound of formula (6), which comprises reacting a compound of formula (4) with a compound of formula (5) via nucleophilic substitution or coupling to give a compound of formula (6):
Figure FDA0002653547580000072
wherein X is F, Cl, Br or I, G1、G2、G3、G4、G5、Y、n、Z、R10And R11As defined in claim 5;
preferably, the compound of formula (4) is reacted with the compound of formula (5) in the presence of an organic solvent and an acid; the organic solvent is preferably a polar solvent, more preferably selected from methanol, ethanol, isopropanol, dimethyl sulfoxide, N-dimethylformamide, N-dimethylacetamide or N-methylpyrrolidone; the acid is preferably concentrated hydrochloric acid, concentrated phosphoric acid, concentrated sulfuric acid or concentrated nitric acid, and more preferably concentrated hydrochloric acid or concentrated phosphoric acid;
the amount of the solvent is 1 to 10mL relative to 1mmol of the compound of formula (4);
the acid is used in an amount of 1 to 10 equivalents with respect to 1 equivalent of the compound of formula (4);
the compound of formula (5) is used in an amount of 1 to 10 equivalents with respect to 1 equivalent of the compound of formula (4).
9. Use of a compound according to any one of claims 1 to 8 or a salt thereof for the preparation of a sulfonamide compound.
10. A process for the preparation of a compound of formula (1) which comprises subjecting a compound of formula (6) and a compound of formula (7) to a nucleophilic substitution reaction to give a compound of formula (1), which reaction is carried out in the presence of a catalyst and optionally an additive or optionally a base:
Figure FDA0002653547580000081
wherein R is1And R2The same or different, each independently selected from hydrogen and C1-C6Alkyl radical, C3-C8Cycloalkyl radical, C6-C20Aryl radical, C5-C20Heteroaryl group, C3-C18Heterocyclic group, C2-C6Alkenyl radical, C2-C6Alkynyl, above C1-C6Alkyl radical, C3-C8Cycloalkyl radical, C6-C20Aryl radical, C5-C20Heteroaryl group, C3-C18Heterocyclic group, C2-C6Alkenyl radical, C2-C6Alkynyl, optionally unsubstituted or substituted with one or more substituents each independently selected from the group consisting of1-C6Alkyl radical, C3-C8Cycloalkyl radical, C6-C20Aryl radical, C5-C20Heteroaryl group, C3-C18Heterocyclic group, C2-C6Alkenyl radical, C2-C6Alkynyl, amino, hydroxyl, mercapto, carboxyl, C1-C6Alkoxy radical, C3-C18Cycloalkoxy, C6-C20Halogenated aryl, C2-C6Alkoxycarbonyl, acyloxy, amido, ureido, C1-C6Alkylsulfonyl radical, C6-C20Arylsulfonyl radical, C1-C6Haloalkyl, F, Cl, Br, I, cyano, nitro, nitroso, thiocyano, isothiocyanato, C1-C6Sulfanyl, C1-C6Sulfoalkyl radical, C3-C8Cycloalkyl radical, C6-C20Aryl radical, C5-C20Heteroaryl group, C3-C18Heterocyclic group, C2-C6Alkenyl radical, C2-C6Alkynyl is taken as a substituent independently or is formed by free combination; or R10And R11Together with the N atom to which they are attached, form a heterocyclic group which may be monocyclic, bicyclic or tricyclic, or may be a fused, bridged or spirocyclic ring, said hetero ringThe heterocyclic group contains only one N atom or 1,2 or 3 additional hetero atoms selected from N, S and O besides the N atom, and the heterocyclic group is unsubstituted or optionally substituted by one or more substituents independently selected from C1-C6Alkyl radical, C3-C8Cycloalkyl radical, C6-C20Aryl radical, C5-C20Heteroaryl group, C3-C18Heterocyclic group, C2-C6Alkenyl radical, C2-C6Alkynyl, amino, hydroxyl, mercapto, carboxyl, C1-C6Alkoxy radical, C3-C8Cycloalkoxy, C2-C6Alkoxycarbonyl, F, Cl, Br, I, cyano, nitro, nitroso, amido, thiocyano, isothiocyanato, ureido, sulfo, alone or in combination; g1、G2、G3、G4、G5、Y、n、Z、R10And R11As defined in claim 5;
the catalyst is a compound shown as a formula (I) or a compound shown as a formula (II) or a combination thereof:
Figure FDA0002653547580000091
in the formulae (I) and (II), R1And R2Are each independently of the others selected from hydrogen, hydroxy, F, Cl, Br, I, C1-C6Alkyl radical, NO2、C1-C6Alkoxy, amino, C1-C6Alkyl monosubstituted amino, C1-C6Alkyl-disubstituted amino, C1-C6Haloalkyl, C1-C6An alkyloxycarbonyl group; or R1And R2Together with the carbon atom to which they are attached form ring a;
the ring A is selected from: a monocyclic or compensated bicyclic aromatic ring having 6-10 carbon atoms; a monocyclic or compensated bicyclic heteroaryl ring having 5-10 ring atoms comprising 1-3 heteroatoms selected from N, O, S and any combination thereof; a monocyclic or fused bicyclic carbocycle having 3-10 carbon atoms; a monocyclic or compensated bicyclic heterocycle having 3-10 ring atoms comprising 1-3 heteroatoms selected from N, O, S and any combination thereof;
said ring A being optionally substituted by one or more than one substituent RaSubstituted, each substituent RaIdentical or different, independently of one another, from the group consisting of hydroxyl, F, Cl, Br, I, C1-C18Alkyl radical, NO2、C1-C18Alkoxy, amino, C1-C6Alkyl monosubstituted amino, C1-C6Alkyl-disubstituted amino, C1-C6Haloalkyl, C1-C6Alkyl oxycarbonyl radical, C6-C10Aryl, benzyl;
R3are respectively selected from hydrogen, hydroxyl, sulfydryl, F, Cl, Br, I and C1-C6Alkyl radical, NO2、C1-C6Alkoxy, amino, C1-C6Alkyl monosubstituted amino, C1-C6Alkyl-disubstituted amino, C1-C6Haloalkyl, C1-C18Alkyloxycarbonyl, oxytris (pyrrolidinyl) phosphonium hexafluorophosphate, oxytris (pyrrolidinyl) phosphonium tetrafluoroborate, oxytris (dimethylamino) phosphonium hexafluorophosphate, oxytris (dimethylamino) phosphonium tetrafluoroborate, oxydi (dimethylamino) carbonium hexafluorophosphate, oxydi (dimethylamino) carbonium tetrafluoroborate, oxydi (pyrrolidinyl) carbonium hexafluorophosphate, oxydi (pyrrolidinyl) carbonium tetrafluoroborate, -OSO2C1-C6Alkyl, -OSO2C1-C8Perfluoroalkyl group, -OSO2C6-C10An aryl group;
preferably, the catalyst is selected from any one of the following compounds or any combination thereof:
Figure FDA0002653547580000101
more preferably, it isThe catalyst is selected from
Figure FDA0002653547580000102
Or a combination thereof;
the additive is a silicon-containing compound selected from the group consisting of:
unsubstituted or substituted trimethylsilyl, C1-C4Alkyl radical, C1-C4Haloalkyl, phenyl, C1-C4Alkoxy or any combination thereof mono-or poly-substituted silane;
unsubstituted or by C1-C4Alkyl radical, C1-C4Haloalkyl, phenyl, C1-C4Alkoxy or any combination thereof mono-or poly-substituted disiloxane;
a compound of formula (III)
Figure FDA0002653547580000103
Wherein the substituent Re、Rf、Rg、Rh、Ri、Rj、RkIdentical or different, independently of one another, from hydrogen, C1-C4Alkyl radical, C1-C4Haloalkyl, phenyl, C1-C4An alkoxy group;
a compound of formula (IV)
Figure FDA0002653547580000104
Wherein R isl、Rm、Rn、Ro、Rp、RqIdentical or different, independently of one another, from hydrogen, C1-C4Alkyl radical, C1-C4Haloalkyl, phenyl, C1-C4An alkoxy group;
a compound of formula (V)
Figure FDA0002653547580000111
Wherein R isr、Rs、Rt、Ru、Rv、Rw、Rx、RySame or differentAnd independently of each other from hydrogen, C1-C4Alkyl radical, C1-C4Haloalkyl, phenyl, C1-C4Alkoxy, n is 1 to 2000, preferably 10 to 1000, more preferably 100-500;
preferably, the additive is selected from (TMS)2O, 1,1,3, 3-tetramethyldisiloxane, methyldiethoxysilane, silica gels, where n is 1-2000, preferably 10-1000, more preferably 100-500C3H9OSi·(CH4OSi)n·C3H9Si or any one or any combination of the following compounds:
Figure FDA0002653547580000112
more preferably, the additive is selected from (TMS)2O, 1,3, 3-tetramethyldisiloxane, methyldiethoxysilane, or any combination thereof;
the alkali is organic alkali or inorganic alkali, and the organic alkali is selected from: r11R12NR13Wherein R is11、R12And R13Independently of one another, from hydrogen, C1-C4An alkyl group; r21R22N-Y-NR23R24Y is C1-C3Alkylene radical, R21、R22、R23And R24Independently of one another, from hydrogen, C1-C4An alkyl group; unsubstituted or substituted by halogen, C1-C4Alkyl-substituted diaza or triazabicyclo C6-C12An olefin;
Figure FDA0002653547580000113
Figure FDA0002653547580000121
Figure FDA0002653547580000122
wherein R is41、R42、R43、R44、R45Independently of one another, from hydrogen, C1-C4An alkyl group;
the inorganic base is selected from carbonates, phosphates, hydrides and C of alkali metals or alkaline earth metals1-C18An alkyl oxide;
preferably, the base is selected from triethylamine, diisopropyldiethylamine, 1, 8-diazabicyclo [5.4.0] undec-7-ene (DBU), 1,5, 7-triazabicyclo [4.4.0] dec-5-ene (TBD), 1, 4-diazabicyclo [2.2.2] octane (DABCO), potassium carbonate, cesium carbonate, potassium phosphate, 2-tert-butylimino-2-diethylamino-1, 3-dimethylperhydro-1, 3, 2-diazaphosphorus (BEMP) and 2-tert-butyl-1, 1,3, 3-tetramethylguanidine (Barton base);
more preferably, the base is triethylamine or diisopropylethylamine;
the catalyst is used in an amount of 0.0001 to 2.0 equivalents with respect to 1 equivalent of the compound of formula (6);
the additive is used in an amount of 0 to 10 equivalents with respect to 1 equivalent of the compound of formula (6);
the base is used in an amount of 0 to 10 equivalents with respect to 1 equivalent of the compound of formula (6);
the amount of the solvent is 1 to 10mL relative to 1mmol of the compound of formula (6);
the compound of formula (7) is used in an amount of 0.2 to 10 equivalents with respect to 1 equivalent of the compound of formula (6).
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