阅读说明：本技术 一种β-羰基砜衍生物及其制备方法和应用 (Beta-carbonyl sulfone derivative and preparation method and application thereof ) 是由 王海 张耀红 于 2019-09-02 设计创作，主要内容包括：本发明公开了一种β-羰基砜衍生物及其制备方法和应用,该制备方法包括以下步骤：以烯烃叠氮与磺酰肼为起始原料,使用CuSO<Sub>4.</Sub>5H<Sub>2</Sub>O为催化剂,水为反应溶剂,反应温度为90℃,反应时间为2-4小时。本发明通过在反应体系中使用催化剂CuSO<Sub>4.</Sub>5H<Sub>2</Sub>O,有效地促进了该反应,抑制了磺酰肼的自身偶联反应,提高了反应的收率；同时,所用的反应试剂及催化剂稳定廉价易得,便于进行大批量的生产,为构建该类结构提供了新的有效途径；而且反应溶剂为水,具有绿色经济环保的优点。此外,活性实验结果表明,产物可以在一定程度上抑制11β-羟基类固醇脱氢酶,因此,该制备方法及其产物在医药领域方面具有重要的应用意义。(The invention discloses a beta-carbonyl sulfone derivatives, process for their preparation and their use, the process comprising the steps of: using alkene azide and sulfonyl hydrazide as starting materials and CuSO 4. 5H 2 O is used as catalyst, water is used as reaction solvent, the reaction temperature is 90 ℃, and the reaction time is 2-4 hours. The invention uses a catalyst CuSO in a reaction system 4. 5H 2 O, effectively promoting the reaction, inhibiting the self-coupling reaction of the sulfonyl hydrazide and improving the yield of the reaction; meanwhile, the used reaction reagent and catalyst are stable, cheap and easy to obtain, and are convenient for mass production, so that a new effective way is provided for constructing the structure; and the reaction solvent is water, so that the method has the advantages of environmental friendliness, economy and environmental friendliness. In addition, the activity experiment result shows that the product can inhibit 11 beta-hydroxysteroid dehydrogenase to a certain extent, so that the preparation method and the product thereof have important application significance in the field of medicine.)

1. A beta-carbonyl sulfone derivative is characterized by having a structure shown as a formula (I):

in formula (I):

R₁is substituted or unsubstituted aryl or C₁～C₄An alkyl radical, wherein the substituents on the aryl radical are selected from C₁～C₄Alkyl, alkoxy, ester group, halogen, nitro, trifluoromethyl or alkanoyl, wherein the number of the substituent can be one or more;

R₂is alkyl, substituted or unsubstituted aryl, wherein the substituent on the aryl is selected from alkyl, alkoxy, aryl, ester group, halogen, nitro or trifluoromethyl, and the number of the substituent can be one or more.

2. The β -carbonyl sulfone derivative of claim 1, wherein R is₁Is substituted or unsubstituted phenyl, and the substituent on the phenyl is selected from one or more of methoxy, methyl, tert-butyl, F, Cl or Br.

3. The β -carbonyl sulfone derivative of claim 1 or 2, wherein R is₂Is substituted or unsubstituted phenyl, naphthyl, thienyl or quinolyl, and the substituent on the aryl is selected from methoxy, methyl, tert-butyl, F, Cl, Br and-NO₂、CF₃Or one or more phenyl groups.

4. A method for producing the β -carbonyl sulfone derivative according to any one of claims 1 to 3, which comprises the steps of: under the action of a copper catalyst, reacting olefin azide and sulfonyl hydrazide in a solvent to realize multi-functionalization of the olefin azide, and after the reaction is completed, performing post-treatment to obtain the beta-carbonyl sulfone derivative;

the structure of the olefin azide is shown as a formula (II):

the structure of the sulfonyl hydrazide is shown as a formula (III):

R₁or R₂Is as defined in any one of claims 1 to 3.

5. The method for producing a β -carbonyl sulfone derivative of claim 4, wherein the molar ratio of the reaction substrates is sulfonyl hydrazide: alkene azide: copper catalyst ═ 1.0: 1.0-1.2: 0.1 to 0.2.

6. The method of claim 4The preparation method of the beta-carbonyl sulfone derivative is characterized in that the copper catalyst is CuSO₄.5H₂O。

7. The method for producing a β -carbonyl sulfone derivative according to claim 4, wherein the solvent is water.

8. The method for producing a β -carbonyl sulfone derivative according to claim 4, wherein the reaction temperature is 90 to 100 ℃ and the reaction time is 2 to 4 hours.

9. Use of a β -carbonyl sulfone derivative according to any of claims 1 to 3 for the preparation of an anti-infective medicament.

Technical Field

The invention belongs to the field of organic synthesis, and particularly relates to a beta-carbonyl sulfone derivative and a preparation method and application thereof.

Background

Sulfones are important sulfur-containing organic compounds, and have activities such as antibiosis, blood coagulation and the like and medicinal values, so the sulfones are widely applied to organic synthesis and synthesis of medicinal intermediates. For example, the penicillsulphone drug (sulbactam) is an irreversible enzyme inhibitor, acts on beta-lactamase, and can competitively inhibit the activity of the enzyme, thereby generating antibacterial and bactericidal biological activity, and is particularly effective for leprosy bacillus. The beta-carbonyl sulfone has many functional groups such as carbonyl, active methylene, sulfone group and the like in the structure, can react with many compounds, participates in various chemical reactions in organic synthesis, plays a very important role, is a very important intermediate in the process of synthesizing natural bioactive molecules and pharmaceutically active molecules, and can be used for synthesizing alkene sulfone, beta-chloro alkene sulfone, thiophene and derivatives thereof, nitrogen-containing heterocyclic compounds, tetra-substituted dihydrofuran derivatives, photochemically active beta-hydroxy sulfone, delta-carbonyl sulfone and aromatic carbonyl compounds. Therefore, the beta-carbonyl sulfone is an important intermediate and has wide application in the fields of pharmaceutical synthesis, biopharmaceuticals and material science, but in the currently reported synthesis method, some strong acid, toxic oxidant or noble metal is often added into a reaction system, or raw materials are difficult to obtain, reaction conditions are harsh, or substituent groups are limited, so that efficient, mild and green reaction conditions are searched for on the basis, novel chemical reactions are developed, and the beta-carbonyl sulfone is always an object required by Cuminum cuminum of organic chemists. In view of the above, the present invention has developed a novel method for synthesizing β -carbonyl sulfone derivatives.

In 2006, Suryakiran N and the like use sulfinate and alpha-haloketone as reaction raw materials, and use PEG-400 polymer carrier or ionic liquid to promote the reaction (Suryakiran N, Reddy T S, Ashalatha K, ethylene. simple polyethylene glycol (PEG-400) protein synthesis of beta-ketosulfofos [ J ]. Tetrahedron Lett,2006 (47): 3853-3856). However, the sulfinate which is the raw material of the reaction is not easy to obtain, the variety is rare, the sulfinate is mainly prepared by sulfonyl chloride, and the yield of the synthesized beta-carbonyl sulfone compound is not high. The specific reaction equation is shown in formula 1-1:

in 2013, Lu Q and the like utilize sulfinic acid, derivatives thereof and unsaturated compounds (mainly alkyne and alkene) as Reaction raw materials to synthesize beta-carbonyl sulfone compounds (Lu Q, Zhang J, Zhao G, et al Dioxyden-Triggered oxidative Radical Reaction: Direct Aerobic differentiation of Terminal alkyl heated beta-Keto sulfonic [ J ]. J.am.chem.Soc.,2013 (135): 11481-11484). Wherein the nitroethane is a solvent and a catalyst, but the nitroethane has pungent taste, sulfinate which is a reaction raw material is not easy to obtain, the variety is rare, in addition, the reaction time is too long, the yield is not high, and is only 39% -57%. The specific reaction equation is shown in formula 1-2:

in 2012, Sreedhar et al first utilized terminal alkynes and sulfonyl chlorides to form β -carbonyl sulfones (Sreedhar B and Rawat V.A. regioselective catalysts-and additive-free from aryl amides and sodium aryl sulfides [ J ] Synlett,2012 (3): 413-417) under the action of a catalyst, which directly utilized sulfonyl chlorides as sulfonation reagents, shortened the reaction steps, reduced the reaction time, but had an irritating taste, and the yield of the reaction was also not high. The specific reaction equation is shown in formulas 1-3:

the Wei topic group in 2013 improves the reaction, and uses sulfonyl hydrazide with low toxicity, wide source and good chemical stabilitySulfonyl hydrazide with olefin in place of sulfonyl chloride as starting material in Cu (OAc)₂Catalytically, beta-carbonyl sulfone (Wei W, Liu C L, Yang D S, et al, Copper-catalyzed directive catalysis of aldehydes with diols and sulphonylhydrazides leading to beta-carbonyl sulfones [ J ] is synthesized by a free radical reaction mechanism]Commun,2013 (49): 10239-10241), but the reaction yield is difficult to control, the reaction time is too long, and the reaction rate is low. The specific reaction equation is shown in formulas 1-4:

in 2008, France sca G et al found that β -carbonyl sulfone compounds could be converted from β -carbonyl sulfide by oxidation (France sca G, Ilaria N, France B, et al.Selective oxidation of sulfides and sulfoxides using 30% of aqueous hydrogen peroxide and silicon-vanadium catalyst [ J ]. J.mol.C.A-chem.2008 (286): 124-127), but the β -carbonyl sulfide as the raw material of this reaction had a smelly egg odor, had a certain toxicity and was not easily synthesized. The specific reaction equation is shown in formulas 1-5:

qingquan Lu et al reported the formation of beta-carbonyl sulfones (Lu Q., Chen J, Liu C, et al.O.) by reacting alpha-bromostyrene with benzenesulfonic acid₂-mediated C(sp2)–X bond oxygenation:autoxidative carbon–heteroatom bond formation using activated alkenes as a linkage[J]RSC adv.,2015,5 (31): 24494-24498), no catalyst is used in the reaction, and the synthesis yield is high. However, the reaction adopts pyridine, tetrahydrofuran and other organic solvents, and has certain toxicity. The specific reaction equation is shown in formulas 1-6:

vinod K et al found that sodium sulfinate and aromatic alcohol acetate can react in water or acetonitrile solution under the catalysis of iodine to obtain beta-carbonyl sulfone (Vinod K, Yadav, Vishun P, et al. molecular iodine mediated oxidative coupling of alcohols with salts to beta-ketosulfonic acids [ J ]. Tetrahedron letters, 2016,57 (21): 2236-2238), which has many advantages: the method does not adopt a metal catalyst, the synthesis method is a one-pot method, the operation is simple and convenient, and the raw materials are cheap and easy to obtain. However, the reaction time is too long, and the specific reaction equation is shown in formulas 1 to 7:

in 2017, Yongping Yu topic group found that the reaction of sulfonyl hydrazide with olefin azide could produce beta-carbonyl sulfone (Chen W-T, liu X-Y, Chen E, Chen B-H, Shao J-A and Yu Y-P.KI-mediated chemical multi-functionalization of vinyl azides: a one-pot and effective approach to beta-keto sulfo-nes and alpha-halo-beta-keto sulfo [ J ], org. chem. Front.,2017,4,1162 QO 1166 DOI:10.1039/C6 00756B), which was mediated by KI, TBHP was a radical initiator, DMSO was a solvent, but when R1 was alkyl only, trace amount of target product was obtained. The specific reaction equation is shown in formulas 1-8:

Yan-Shi Xiong et al have recently found that aromatic alkynoic acids react with sodium sulfonate to give β -carbonyl sulfones (Xiong Y-S, Weng J, and Lu G. manganese (III) -mediated and-catalyzed carboxylic elimination sulfones of arylprobiotic acids with sodium sulfides in water [ J ]. adv. Synth. Catal,2018,360 (8): 1611-1616) in water solvent under manganese mediation, which has mild reaction conditions and short reaction time, but the reaction yield is not high, as shown in the following specific equations 1-9:

disclosure of Invention

The invention provides a beta-carbonyl sulfone derivative and a preparation method and application thereof, wherein the beta-carbonyl sulfone derivative has certain 11 beta-hydroxysteroid dehydrogenase (11 beta-HSD 1) inhibition activity and has the potential of being used as an anti-infective drug; the raw materials used in the preparation method are simple, stable and easily available, the reaction conditions are mild, and water is used as a reaction solvent, so that the preparation method is economic and environment-friendly.

A beta-carbonyl sulfone derivative has a structure shown in formula (I):

in formula (I):

R₁is substituted or unsubstituted aryl or C₁～C₄An alkyl radical, wherein the substituents on the aryl radical are selected from C₁～C₄Alkyl, alkoxy, ester group, halogen, nitro, trifluoromethyl or alkanoyl, and the number of the substituents may be one or more.

R₂Is alkyl, substituted or unsubstituted aryl, wherein the substituent on the aryl is selected from alkyl, alkoxy, aryl, ester group, halogen, nitro or trifluoromethyl, and the number of the substituent can be one or more.

The compounds have 11 beta-hydroxysteroid dehydrogenase (11 beta-HSD 1) inhibition activity and potential as anti-infective drugs through biological activity tests on the beta-carbonyl sulfone derivatives;

in the formula (I), preferably, R₁Is substituted or unsubstituted phenyl, and the substituent on the phenyl is selected from methoxy, methyl, tert-butyl, F, Cl, Br and-NO₂、CF₃Or a phenyl group.

Preferably, R₂Is substituted or unsubstituted phenyl, naphthyl, thienyl or quinolyl, wherein the substituent on the phenyl is selected from methoxy, methyl, tert-butyl, F, Cl, Br and-NO₂、CF₃Or a phenyl group.

The invention also provides a preparation method of the beta-carbonyl sulfone derivative, which is characterized by comprising the following steps: the beta-carbonyl sulfone derivative is obtained by taking hydrocarbon azide and sulfonyl hydrazide as starting raw materials, reacting at the temperature of 90 ℃ for 2-4 hours under the action of a copper catalyst and water, and performing post-treatment after complete reaction.

The reaction equation is as follows:

in recent years, sulfonyl hydrazide has been widely used in organic chemistry, bio-organic chemistry and pharmaceutical chemistry to synthesize functional structures of various bioactive compounds, and becomes a novel, cheap and easily available synthetic reagent. Compared with aryl sulfonyl chloride which is easy to hydrolyze to release HCl, the sulfonyl hydrazide is more stable and easy to process and is an ideal aryl source for constructing C-C bonds. The invention adopts CuSO₄.5H₂The O catalytic reaction successfully realizes the multi-functionalization reaction of the olefin azide and has important application significance.

The type of copper catalyst, which is preferably CuSO, has a critical influence on the reaction efficiency₄.5H₂O, in this case, the reaction yield is high.

The choice of the reaction medium will also have a large influence on the reaction result, and preferably the reaction solvent is water.

Preferably, the reaction temperature is 90 ℃ and the reaction time is 2-4 hours.

The invention also provides application of the beta-carbonyl sulfone derivative in preparing anti-infective medicaments.

Compared with the prior art, the invention has the beneficial effects that:

(1) by using CuSO₄.5H₂The O catalytic reaction successfully realizes the multi-functionalization reaction of the olefin azide, the reaction reagent is stable and easy to obtain, the reaction condition is mild, the reaction effect is good, and the reaction solvent is water, so that the method is green, economic and environment-friendly, and has important application significance.

(2) The beta-carbonyl sulfone derivative obtained by the method has certain inhibitory activity to 11 beta-HSD 1, and has the potential of being used as an antibacterial drug.

Detailed Description

The general synthesis procedure is as follows:

a magnetic stirrer was added to a 25ml pressure-resistant test tube, sulfonyl hydrazide (1mmol) and olefin azide (1.2mmol) were added to the 25ml pressure-resistant test tube, a catalyst (10% mol) and a solvent (about 10ml) were further added, the reaction was carried out at a certain temperature for 2 to 4 hours, and Thin Layer Chromatography (TLC) tracing was carried out until the reaction was completed. After the reaction is finished, adding saturated NaCl aqueous solution and ethyl acetate into the reaction system for extraction, taking an organic layer, extracting for 3 times, combining the organic layers, and using anhydrous Na₂SO₄Drying, vacuum evaporating solvent to obtain crude product, and purifying by column chromatography to obtain pure target product.

The present invention will be described in detail with reference to specific examples.