CN107163062A - A kind of sulphonyl lactone compound and preparation method thereof - Google Patents

A kind of sulphonyl lactone compound and preparation method thereof Download PDF

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CN107163062A
CN107163062A CN201710507185.9A CN201710507185A CN107163062A CN 107163062 A CN107163062 A CN 107163062A CN 201710507185 A CN201710507185 A CN 201710507185A CN 107163062 A CN107163062 A CN 107163062A
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sulphonyl
phenyl
lactone compound
heteroaromatic
preparation
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CN107163062B (en
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秦华利
陈兴
查高峰
冷静
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Wuhan University of Technology WUT
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D497/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having oxygen and sulfur atoms as the only ring hetero atoms
    • C07D497/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having oxygen and sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D497/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D327/00—Heterocyclic compounds containing rings having oxygen and sulfur atoms as the only ring hetero atoms
    • C07D327/02—Heterocyclic compounds containing rings having oxygen and sulfur atoms as the only ring hetero atoms one oxygen atom and one sulfur atom
    • C07D327/06—Six-membered rings

Abstract

The invention discloses a kind of sulphonyl lactone compound and preparation method thereof.Comprise the following steps：Using 2 aryl vinyl sulfuryl fluorides or 2 alkenyl vinyl base sulfuryl fluorides as raw material, mixed with pyrazolone, diketone or the diester of the substituted-phenyl containing different functional groups, add base catalyst, additive and solvent mixing, react at room temperature 3 96h, isolate and purify, obtain ester products in sulphonyl.Product produced by the present invention is sulphonyl lactone compound, is, by simple Michael addition reaction, in the presence of auxiliary alkali, to slough a molecule hydrogen fluoride and occur what cyclization effect was obtained.There are lot of documents and research to show, many all has various bioactivity containing pyrazolone structure or sulphonyl lactone structure, and such portion of product contains pyrazole ring and sulphonyl lactonic ring simultaneously, it is likely that with certain bioactivity, by follow-up study and optimization, there is potential prospect in medicine.

Description

A kind of sulphonyl lactone compound and preparation method thereof
Technical field
The present invention relates to field of pharmaceutical chemistry technology, and in particular to a kind of sulphonyl lactone compound and preparation method thereof.
Background technology
Sulphonyl lactone (Sultones) is a kind of important heterocyclic compound containing sulphur atom, most sulphonyl lactone Be four arrive hexatomic ring, a small number of is heptatomic ring or bigger ring.In organic synthesis, sulphonyl lactone compound is a kind of valuable Heterocyclic intermediate, in the presence of nucleophile, its carbon-oxygen bond is easy to be broken, and will contain sulfonyl function Alkyl chain be incorporated into other compounds, therefore it may be used as Sulfonylalkyl reagent (Sulfoalkylatingagents).In pharmaceutical chemical research, many sulphonyl lactone compounds have certain biology Activity, is concentrated mainly on antiviral activity (Antiviral activities), skin sensitization (Skin Sensitization) and toxicology (Toxicological) research (Chem.Rev.2012,112,5339), such as the U.S. Wuerzburg university Karma Lhasa seminar reports a kind of pentacyclic unsaturated sulphonyl lactone derivatives, is effective and selective Non-nucleoside reverse transcriptase inhibitor, available for treatment I types AIDS (J.Med.Chem.2004,47,3418).
In various heterocyclic compounds, nitrogenous pentacyclic pyrazolone (Pyrazolones) derivative is caused widely Concern, pyrazolone module be many natural products with bioactivity a part (Eur.J.Med.Chem.2013,69, 735).Inherently a kind of medicine of pyrazolone medicine Edaravone simple in construction, for treating neuropathy caused by cerebral infarction Become, clinical treatment is widely used in injection at present；Pyrazolone and its derivative can be with carbon-hydrogen, oxygen-hydrogen, three kinds of shapes of nitrogen-hydrogen Formula is present, therefore the nucleophilic addition that can be carried out on various chemical reactions, especially carbon easily occurs.By to pyrazolone And its research of derivative is found, many such compounds have various bioactivity, such as can be used as analgesic-antipyretic (J.Agric.Food Chem.2010,58,5531), insecticide (Chem.Abstr.1984,101,191894), ampa receptor Activator (Chem.Abstr.2010,154,30328), PERK (endocytoplasmic reticulum protein kinase) inhibitor (J.Med.Chem.2015,58,1426), or with active anticancer (Eur.J.Med.Chem.2014,74,440), anti-high blood Sugared activity (J.Med.Chem.1996,39,3920), immunologic competence (J.Med.Chem.1981,24,830), anti-H1N1 and H5N1 virus activity (Org.Lett.2014,16,5060) etc..Therefore, pyrazolone is built by a series of chemical reaction to derive Thing, with potential bioactivity and application value.
The content of the invention
The present invention is intended to provide a kind of have the multifarious sulphonyl lactone compound of functional group, the series compound has official The characteristics of diversity is strong, quantity is more can be rolled into a ball.Simultaneously be easy to get there is provided a kind of raw material, reaction condition gently, good reaction selectivity, production Rate is high, instrument and equipment requires low and simple to operate synthetic method, is expected to be used for preparing a variety of sulphonyl lactone compounds on a large scale, The research of bioactivity is carried out to it, applied to fields such as organic synthesis, pharmaceutical chemistry.
It is as follows using technical scheme to reach above-mentioned purpose：
A kind of preparation method of sulphonyl lactone compound, comprises the following steps：
Using 2- aryl vinyls sulfuryl fluoride or 2- alkenyls-vinvlsulfonamido fluorine as raw material, with substituted benzene containing different functional groups Pyrazolone, diketone or the diester mixing of base, add base catalyst, additive and solvent mixing, react at room temperature 3-96h, separate pure Change, obtain ester products in sulphonyl.
By such scheme, the 2- aryl vinyls sulfuryl fluoride has following structural formula：
Wherein, (hetero) aryl of formula 1 be phenyl, substituted-phenyl, fused ring aryl, substitution fused ring aryl, heteroaromatic or Person's heteroaromatic deriveding group.
By such scheme, the 2- alkenyls-vinvlsulfonamido fluorine has following structural formula：
Wherein, (hetero) aryl of formula 2 be phenyl, substituted-phenyl, fused ring aryl, substitution fused ring aryl, heteroaromatic or Person's heteroaromatic deriveding group.
By such scheme, the pyrazolone has following structural formula：
Wherein, the R of formula 31、R2Respectively hydrogen, halogen, alkyl, substitution alkyl, phenyl, substituted-phenyl, heteroaromatic or virtue Heterocyclic derivatives group.
By such scheme, the diketone or diester have following structural formula：
Wherein, the R of formula 41、R2Respectively hydrogen, halogen, alkyl, substitution alkyl, phenyl, substituted-phenyl, heteroaromatic or virtue Heterocyclic derivatives group.
By such scheme, the base catalyst is DBU, TMEDA, DMAP, DABCO, Et3N, DIEA or NaCO3。
It is preferred that base catalyst is DBU.
By such scheme, the additive is NaHCO3、KHCO3、CaHCO3Or NH4HCO3。
Preferable additives are NaHCO3。
By such scheme, 2- aryl vinyls sulfuryl fluoride or the 2- alkenyl-vinvlsulfonamido fluorine, take containing different functional groups Mol ratio for the pyrazolone or diketone or diester, base catalyst, additive of phenyl is 1:(1~10):(0.000001~ 0.6):(1~2).
It is preferred that 2- aryl vinyls sulfuryl fluoride or 2- alkenyls-vinvlsulfonamido fluorine, the pyrrole of the substituted-phenyl containing different functional groups Oxazolone or diketone or diester, base catalyst, the mol ratio of additive are 1:1:(0.05 or 0.2):1.
By such scheme, the solvent is DCM, DMSO, DMF, MeOH, MeCN, Acetone or THF；Or above-mentioned solvent with The mixed solvent of other organic solvents or water.
Preferred solvent is dichloromethane.
The sulphonyl lactone compound as made from such scheme, there is following structural：
(hetero) aryl is that phenyl, substituted-phenyl, fused ring aryl, substitution fused ring aryl, heteroaromatic or virtue are miscellaneous in formula Ring deriveding group, R1、R2Respectively hydrogen, halogen, alkyl, substituted-phenyl, heteroaromatic or heteroaromatic deriveding group.
Gained compound can be applied to antibacterial, anti-inflammatory, antipyretic-antalgic, it can also be used to the research and development of antineoplastic.
Relative to prior art, have the beneficial effect that：
Product produced by the present invention is sulphonyl lactone compound, is by simple Michael addition reaction, in auxiliary alkali In the presence of, slough a molecule hydrogen fluoride and occur what cyclization effect was obtained.There are lot of documents and research to show that many contains pyrazoles Ketone structure or sulphonyl lactone structure all have various bioactivity, and such portion of product contains pyrazole ring and sulphur simultaneously Acyl lactone ring, it is likely that with certain bioactivity, by follow-up study and optimization, there is potential prospect in medicine.
There is not the method for synthesizing pyrazole and sulphonyl lactone compound also at present, the present invention innovatively constructs a kind of reaction Mild condition (carries out under room temperature and air conditionses and only needs to add alkali and auxiliary alkali to react), wide application range of substrates (being resistant to most functional groups), instrument and equipment requires low, and simple to operate and yield is high, and (most of yield can reach More than 85%), raw material is (according to Angew.Chem.Int.Ed.2017, largely being prepared described in 56,4849.) simple and easy to get, possesses The condition that laboratory is largely prepared and industrial production is amplified.
Embodiment
Following examples further explain technical scheme, but not as limiting the scope of the invention.
Embodiment 1
In 250mL reaction bulbs, 2- phenyl-ethenyls-sulfuryl fluoride (3.72g, 20mmol), 1- phenyl -3- methyl -5- is added Pyrazolone (3.48g, 20mmol), DBU (0.15g, 1.0mmol, 5mol%), NaHCO3(1.68g,20mmol),DCM (100mL), reacts 24h at room temperature, and dichloromethane is reclaimed in reaction solution vacuum distillation, and residue is purified with silica gel column chromatography (to be eluted Agent is petroleum ether:Ethyl acetate=5:1 (v/v)), produce 5- methyl -4,7- diphenyl -4,7- dihydro -3H- [1,2] sulphur oxa- Ring [6,5-c] pyrazoles 2,2- dioxide (6.40g, 94%yield).Also reaction solution can be filtered using silica gel, filtrate washing, Petroleum ether crystallization is added after being concentrated to dryness after drying and obtains this product.Mp 139-140℃.1HNMR(400MHz,DMSO-d6)δ7.61 (d, J=8.1Hz, 2H), 7.56 (d, J=7.3Hz, 2H), 7.46 (d, J=7.1Hz, 2H), 7.42-7.33 (m, 4H), 4.55 (dd, J=10.7Hz, J=5.7Hz, 1H), 4.47 (dd, J=13.9Hz, J=5.7Hz, 1H), 4.03 (dd, J=13.9Hz, J =10.7Hz, 1H), 1.59 (s, 3H)13C NMR(126MHz,CDCl3)δ147.0,144.0,138.2,137.1,129.5, 129.3,128.5,128.0,127.2,121.6,99.0,52.1,37.9,13.6.ESI-MS HRMS calculated for C18H16N2O3S[M+1]+341.0954,found 341.0954.
Embodiment 2：
In 250mL reaction bulbs, addition 2- thiophenyl-ethenyls sulfuryl fluoride (3.84g, 20mmol), 1- phenyl -3- methyl - 5- pyrazolones (3.48g, 20mmol), DBU (0.15g, 1.0mmol, 5mol%), NaHCO3(1.68g,20mmol),DCM (100mL), reacts 24h at room temperature, and dichloromethane is reclaimed in reaction solution vacuum distillation, and residue is purified with silica gel column chromatography (to be eluted Agent is petroleum ether:Ethyl acetate=5:1 (v/v)), produce 5- methyl -7- phenyl -4- (thiophene -3- alkyl) -4,7- dihydros -3H- [1,2] sulphur oxa- ring [6,5-c] pyrazoles 2,2- dioxide (6.10g, 88%yield).Also reaction solution can be used silica gel mistake Filter, filtrate washing adds petroleum ether crystallization and obtains this product after being concentrated to dryness after drying.Mp 138-139℃.1H NMR (500MHz,CDCl3) δ 7.66 (d, J=7.8Hz, 2H), 7.47 (t, J=7.7Hz, 2H), 7.35-7.32 (m, 2H), 7.08- 7.07 (m, 1H), 7.03-7.01 (m, 1H), 4.88 (dd, J=10.9Hz, J=5.9Hz, 1H), 3.81 (dd, J=14.2Hz, J =5.9Hz, 1H), 3.50 (dd, J=14.2Hz, J=10.9Hz, 1H), 1.88 (s, 3H)13C NMR(126MHz,CDCl3)δ 147.1,143.3,141.4,137.0,129.3,127.3,127.3,126.7,126.1,121.7,99.1,52.4,33.0, 13.4.ESI-MS HRMS calculated for C16H14N2O3S2[M+1]+347.0519,found 347.0519.
Embodiment 3：
In 250mL reaction bulbs, (1E, 3E) -4- phenyl -1,3- diene -1- sulfuryl fluorides (4.24g, 20mmol), 1- benzene are added Base -3- Methyl-5-pyrazolones (3.48g, 20mmol), DBU (0.61g, 4.0mmol, 20mol%), NaHCO3(1.68g, 20mmol), DCM (100mL), reacts 24h at room temperature, and dichloromethane, residue silica gel column layer are reclaimed in reaction solution vacuum distillation (eluant, eluent is petroleum ether for analysis purifying:Ethyl acetate=5:1 (v/v)), (E) -5- methyl -7- phenyl -4- styryl -4 are produced, 7- dihydros -3H- [1,2] sulphur oxa- ring [6,5-c] pyrazoles -2,2- dioxide (6.00g, 82%yield).Also can be by reaction solution Filtered using silica gel, filtrate washing, petroleum ether crystallization is added after being concentrated to dryness after drying and obtains this product.1H NMR(500MHz, CDCl3) δ 7.65 (d, J=7.8Hz, 2H), 7.47 (t, J=7.6Hz, 2H), 7.42 (d, J=7.3Hz, 2H), 7.38-7.30 (m, 4H), 6.74 (d, J=15.7Hz, 1H), 6.24 (dd, J=15.7Hz, J=9.0Hz, 1H), 4.18-4.14 (m, 1H), (s, the 3H) .13C of 3.66 (dd, J=14.2Hz, J=6.1Hz, 1H), 3.39 (dd, J=14.2Hz, J=9.0Hz, 1H), 2.23 NMR(126MHz,CDCl3)δ147.2,143.4,137.0,135.8,134.2,129.3,128.9,128.5,127.2, 126.9,125.8,121.7,97.9,50.035.5,13.8.ESI-MS HRMS calculated for C20H18N2O3S[M +1]+367.1111,found 367.1111.
Embodiment 4
In 250mL reaction bulbs, add ((E) -2- cyclopentene -1- sulfuryl fluorides (3.53g, 20mmol), 1- phenyl -3- methyl - 5- pyrazolones (3.48g, 20mmol), DBU (0.61g, 4.0mmol, 20mol%), NaHCO3(1.68g,20mmol),DCM (100mL), reacts 24h at room temperature, and dichloromethane is reclaimed in reaction solution vacuum distillation, and residue is purified with silica gel column chromatography (to be eluted Agent is petroleum ether:Ethyl acetate=5:1 (v/v)), produce 4- cyclopentene -5- methyl -7- phenyl -4,7- dihydros -3H- [1,2] sulphur Oxa- ring [6,5-c] pyrazoles -2,2- dioxide (4.82g, 73%yield).Also reaction solution can be filtered using silica gel, filtrate Washing, adds petroleum ether crystallization and obtains this product after being concentrated to dryness after drying.Mp 101-102℃.1H NMR(500MHz,CDCl3)δ 7.64 (d, J=7.6Hz, 2H), 7.47 (t, J=7.8Hz, 2H), 7.33 (t, J=7.5Hz, 1H), 5.84 (s, 1H), 4.28 (dd, J=10.9Hz, J=6.0Hz, 1H), 3.55 (dd, J=14.0Hz, J=6.0Hz, 1H), 3.36 (dd, J=14.0Hz, J =10.9Hz, 1H), 2.48-2.44 (m, 2H), 2.28-2.25 (m, 2H), 2.18 (s, 3H), 2.03-1.97 (m, 2H)13C NMR(126MHz,CDCl3)δ146.8,143.6,139.6,137.1,131.0,129.3,127.1,121.6,97.9,48.7, 33.6,32.3,31.5,23.4,13.4.ESI-MS HRMS calculated for C17H18N2O3S[M+1]+331.1111, found 331.1110.
Method synthesizing pyrazole and sulphonyl lactone compound, its typical structure and the following institute of reaction yield using the present invention Show, disclosed sulphonyl lactone molecule structural formula is used as limiting the scope of the invention.
Disclosure of the invention has multifarious sulphonyl lactone compound of functional group and preparation method thereof.The serial chemical combination Thing has that functional group's diversity is strong, quantity is more, and provide it is a kind of there is raw material to be easy to get, reaction condition is gentle, good reaction selectivity, Yield is high, instrument and equipment requires low and simple to operate method.Such compound is expected to be used for preparing on a large scale in a variety of sulphonyl Ester compounds, the research of bioactivity is carried out to it, applied to fields such as organic synthesis, pharmaceutical chemistry.

Claims (10)

1. a kind of preparation method of sulphonyl lactone compound, it is characterised in that comprise the following steps：
Using 2- aryl vinyls sulfuryl fluoride or 2- alkenyls-vinvlsulfonamido fluorine as raw material, with the substituted-phenyl containing different functional groups Pyrazolone, diketone or diester mixing, add base catalyst, additive and solvent mixing, react at room temperature 3-96h, isolate and purify, obtain Ester products in sulphonyl.
2. the preparation method of sulphonyl lactone compound as claimed in claim 1, it is characterised in that the 2- aryl vinyls sulphonyl Fluorine has following structural formula：
Wherein, (hetero) aryl of formula 1 is phenyl, substituted-phenyl, fused ring aryl, substitution fused ring aryl, heteroaromatic or virtue Heterocyclic derivatives group.
3. the preparation method of sulphonyl lactone compound as claimed in claim 1, it is characterised in that the 2- alkenyls-vinvlsulfonamido Fluorine has following structural formula：
Wherein, (hetero) aryl of formula 2 is phenyl, substituted-phenyl, fused ring aryl, substitution fused ring aryl, heteroaromatic or virtue Heterocyclic derivatives group.
4. the preparation method of sulphonyl lactone compound as claimed in claim 1, it is characterised in that the pyrazolone has following knot Structure formula：
Wherein, the R of formula 31、R2Respectively hydrogen, halogen, alkyl, substitution alkyl, phenyl, substituted-phenyl, heteroaromatic or heteroaromatic Deriveding group.
5. the preparation method of sulphonyl lactone compound as claimed in claim 1, it is characterised in that the diketone or diester have with Lower structural formula：
Wherein, the R of formula 41、R2Respectively hydrogen, halogen, alkyl, substitution alkyl, phenyl, substituted-phenyl, heteroaromatic or heteroaromatic Deriveding group.
6. the preparation method of sulphonyl lactone compound as claimed in claim 1, it is characterised in that the base catalyst be DBU, TMEDA、DMAP、DABCO、Et3N, DIEA or NaCO3。
7. the preparation method of sulphonyl lactone compound as claimed in claim 1, it is characterised in that the additive is NaHCO3、 KHCO3、CaHCO3Or NH4HCO3。
8. the preparation method of sulphonyl lactone compound as claimed in claim 1, it is characterised in that the 2- aryl vinyls sulphonyl Fluorine or 2- alkenyls-vinvlsulfonamido fluorine, the pyrazolone of the substituted-phenyl containing different functional groups or diketone or diester, base catalyst, add Plus the mol ratio of agent is 1:(1~10):(0.000001~0.6):(1~2).
9. the preparation method of sulphonyl lactone compound as claimed in claim 1, it is characterised in that the solvent be DCM, DMSO, DMF, MeOH, MeCN, Acetone or THF；Or above-mentioned solvent and other organic solvents or the mixed solvent of water.
10. sulphonyl lactone compound made from claim 1 methods described, it is characterised in that with following structural：
(hetero) aryl is that phenyl, substituted-phenyl, fused ring aryl, substitution fused ring aryl, heteroaromatic or heteroaromatic are spread out in formula Raw group, R1、R2Respectively hydrogen, halogen, alkyl, substituted-phenyl, heteroaromatic or heteroaromatic deriveding group.
CN201710507185.9A 2017-06-28 2017-06-28 A kind of sulphonyl lactone compound and preparation method thereof Expired - Fee Related CN107163062B (en)

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