CN105017155A - Tricyclic diterpene pyrazole derivative and preparation method and application thereof - Google Patents
Tricyclic diterpene pyrazole derivative and preparation method and application thereof Download PDFInfo
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- CN105017155A CN105017155A CN201410153124.3A CN201410153124A CN105017155A CN 105017155 A CN105017155 A CN 105017155A CN 201410153124 A CN201410153124 A CN 201410153124A CN 105017155 A CN105017155 A CN 105017155A
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- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
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Abstract
The invention relates to a tricyclic diterpene pyrazole derivative as shown in the formula (I) and a preparation method thereof. Geraniol epoxy acetate (a compound 1) and a coupled product (a compound 3) of 4-methoxyl benzylmagnesium chloride (a compound 2) undergo a ring closing reaction so as to obtain a compound 4; and bromine or multiple alkyl substituents are introduced into a C ring (benzene ring) of the compound 4 and a pyrazolone ring is introduced into an A ring through steps of IBX oxidation, C-2 formylation, pyrazolo ring so as to obtain the tricyclic diterpene pyrazole derivative as shown in the formula (I). The invention also discloses an application of the tricyclic diterpene pyrazole derivative as shown in the formula (I) in the preparation of antibiotic drugs.
Description
Technical field
The invention belongs to the technical field of medicine and Synthesis and applications thereof, be specifically related to a kind tricyclic diterpene and pyrazole derivatives and preparation method thereof and the application in preparation antibacterials.
Background technology
Society, antibiotic excessive use has expedited the emergence of a lot of endurance strain, and the resistance of bacterium is considered to the serious threat to human health.Streptococcus aureus (Staphylococcus aureus) is a kind of ball-type bacterium of Gram-positive.It is in institute and one of most popular pathogenic agent of Nosocomial Infections, can cause suppuration, otitis media, sepsis, enteritis, sinusitis paranasal sinusitis, osteomyelitis, the pneumonia even disease such as septicemia after infection.A lot of drug-fast mutation is had, such as methicillin-resistant staphylococcus aureus (Methicillin-resistent Staphylococcus aureus, MRSA) in streptococcus aureus.MRSA can resist the microbiotic such as beta-lactam, fluoroquinolones, Macrolide, aminoglycoside and tetracyclines, and its infection is the most scabrous clinical problem in world wide.The whole world is infectd extra cost at treatment MRSA every year and is reached 30-40 hundred million dollars (Journal of Medicinal Chemistry, 2014,57,1609-1615).Minority microbiotic such as vancomycin (vancomycin), linezolid (Linezolid), daptomycin (daptomycin), CPT (ceftaroline) are the last line of defenses that treatment MRSA infects.But, occurred at present declining to vancomycin sensitive the staphylococcus aureus strains of even resistance, also occurred case (Journal of Medicinal Chemistry, 2013 of linezolid and the failure of daptomycin clinical treatment, 56,3257-3272.).The anti-microbial activity of natural tricyclic diterpene compound as totarol, Salvin and ferruginol etc. has been proved, but from plant, extract tricyclic diterpene compound often few, the purification difficult of content.Building novel class tricyclic diterpene compound for the research and development of antibacterials by the method for organic synthesis is a kind of more efficiently methods.
Summary of the invention
An object of the present invention is to provide a class class tricyclic diterpene and pyrazole derivatives, and its structure is such as formula shown in (I):
Wherein, R=-H ,-CH
2cH
3,-CH
2cH
2cH
3,-CH
2cH
2cH
2cH
3,-CH=CH
2,-C (CH
3)=CH
2,-CH (CH
3)
2,-Br.
In the present invention, the class tricyclic diterpene corresponding respectively with above-mentioned substituting group pyrazole derivatives are: compound 7,24,25,26,36,37,38,42, and its structural formula is as follows respectively.
Another object of the present invention is to provide formula (I) class tricyclic diterpene and the preparation method of pyrazole derivatives; ring closure reaction is there is and obtains compound 4 in Geraniol epoxy acetic ester (compound 1) with the coupled product (compound 3) of 4-methoxy-benzyl magnesium chloride (compound 2); its C ring (phenyl ring) introduces bromine or multiple alkyl substituent, A ring through IBX oxidation, C-2 position formylation the steps such as pyrazole ring introduce pyrazole ring, obtains class tricyclic diterpene shown in formula (I) and pyrazole derivatives.
Formula (I) class tricyclic diterpene the preparation method of pyrazole derivatives comprises following synthetic route:
Route 1, preparation class tricyclic diterpene pyrazole derivatives 7
Compound 1 and compound 2 generate compound 3 through linked reaction under the catalysis of tetrachloro copper lithium; compound 3 is facilitated lower generation ring closure reaction in methylaluminum dichloride and is generated compound 4; compound 4 is oxidized to obtain compound 5 through IBX; compound 6 is obtained after the C-2 position formylation of compound 5; compound 6 and hydrazine hydrate are obtained by reacting class tricyclic diterpene and pyrazole derivatives 7; wherein, R=-H.
The reaction scheme of described preparation method is as following:
Route 2, preparation class tricyclic diterpene pyrazole derivatives 24,25,26
Compound 4 and acetic anhydride obtain compound 8, compound 8 respectively with Acetyl Chloride 98Min., propionyl chloride, butyryl chloride reacting generating compound 9,10,11, then compound 12,13,14 is obtained respectively through Pd/C hydrogenation, compound 15,16,17 is obtained through hydrolysis reaction by compound 12,13,14, then after IBX oxidation, compound 18,19,20 is obtained, compound 21,22,23 is reacted to obtain with ethyl formate, class tricyclic diterpene is obtained by reacting and pyrazole derivatives 24,25,26 respectively by compound 21,22,23 and hydrazine hydrate, wherein, R is respectively-CH
2cH
3,-CH
2cH
2cH
3,-CH
2cH
2cH
2cH
3.
The reaction scheme of described preparation method is as following:
Route 3, preparation class tricyclic diterpene pyrazole derivatives 36,37,38
Compound 9 obtains compound 27 through hydrolysis reaction, compound 27 obtains compound 28,29 with sodium borohydride and methyl chloride reactive magnesium respectively, then dewater to obtain compound 30,31 under Catalyzed by p-Toluenesulfonic Acid, compound 32,33 is obtained through IBX oxidation by compound 30,31, then compound 34,35 is reacted to obtain with ethyl formate, compound 34,35 obtains class tricyclic diterpene and pyrazole derivatives 36,37 with hydrazine hydrate generation ring closure reaction respectively, and wherein, R is respectively-CH=CH
2,-C (CH
3)=CH
2.
Further, compound 37 obtains class tricyclic diterpene and pyrazole derivatives 38 after Pd/C hydrogenation, and wherein, R is-CH (CH
3)
2.
The reaction scheme of described preparation method is as following:
Route 4, preparation class tricyclic diterpene pyrazole derivatives 42
Compound 4 and bromine react to obtain compound 39, are then oxidized to obtain compound 40 through IBX, the C-2 position of compound 40 after formylation compound 41, then react to obtain class tricyclic diterpene pyrazole derivatives 42 with hydrazine hydrate, wherein, R is-Br.
The reaction scheme of described preparation method is as following:
In preparation method of the present invention, respond all with TLC come tracking and measuring reaction performance level, after completion of the reaction one adopt post-treating method comprise suction filtration, recrystallization, extraction, distillation, column chromatography for separation etc.Final product nuclear magnetic resonance spectrum is verified.
Class tricyclic diterpene of the present invention the advantage of pyrazole derivatives and preparation method thereof comprise, raw materials used cheap and easy to get, pass through Li
2cuCl
4linked reaction under catalysis and MeAlCl
2ring closure reaction under catalysis constructs class tricyclic diterpene compound 4 efficiently, and phenyl ring methoxyl group ortho position is introduced after different substituents and introduced pyrazole ring in C-2, C-3 position, has synthesized the class tricyclic diterpene of a series of novel structure and pyrazole derivatives.Preparation method's synthetic route of the present invention is short, reaction conditions is gentle, environmental friendliness, agents useful for same low price.
Present invention also offers formula (I) class tricyclic diterpene and the application of pyrazole derivatives in preparation antibacterials.Formula (I) class tricyclic diterpene pyrazole derivatives has good bacteriostatic activity, can be used as fungistat.Class tricyclic diterpene shown in formula (I) pyrazole derivatives has good inhibit activities to streptococcus aureus newman bacterial strain, simultaneously to some Resistant strain as NRS-1 bacterial strain (streptococcus aureus of aminoglycoside-resistant microbiotic and tsiklomitsin), NRS-271 bacterial strain (streptococcus aureus of methicillin-resistant and Linezolid), NRS-70 bacterial strain (streptococcus aureus of resistance to erythromycin and Trobicin), NRS-100 bacterial strain (streptococcus aureus of resistance to Prostaphlin and tsiklomitsin), NRS-108 bacterial strain (streptococcus aureus of resistance to gentamicin) all has inhibit activities to a certain degree, as shown in table 1.Wherein, the inhibition of compound 24,25,26 pairs of newman bacterial strains is remarkable, and MIC (minimum inhibitory concentration, minimum inhibitory concentration) is respectively 1.25-1.5,1-1.25,1-1.25 μ g/mL; Compound 38 and 42 has significant inhibit activities to five kinds of drug-resistant S. aureus NRS-1, NRS-271, NRS-70, NRS-100, NRS-108 bacterial strains, and MIC is respectively 1.56-3.12,3.12-6.25,0.7-1.56,1.56-3.12,1.56-3.12 μ g/mL and 1.56-3.12,1.56-3.12,1.56-3.12,1.56-3.12,1.56-3.12 μ g/mL.Experiment shows, formula (I) class tricyclic diterpene pyrazole derivatives can be used as potential antibacterials, has applications well prospect.
Embodiment
In conjunction with following specific embodiment, the present invention is described in further detail, and protection content of the present invention is not limited to following examples.Under the spirit and scope not deviating from inventive concept, the change that those skilled in the art can expect and advantage are all included in the present invention, and are protection domain with appending claims.Implement process of the present invention, condition, reagent, experimental technique etc., except the following content mentioned specially, be universal knowledege and the common practise of this area, the present invention is not particularly limited content.In following embodiment, compound structure is by nmr determination; Reagent provides primarily of Shanghai traditional Chinese medicines chemical reagents corporation; Purifying products is mainly through column chromatography, and silica gel (200-300) is produced by Haiyang Chemical Plant, Qingdao.
Embodiment 1: the preparation of compound 7
By starting compound 1 (9.04g, 42.6mmol) and Li
2cuCl
4(34mL, 0.1M in THF) is dissolved in 60mL THF, and cryosel bath is cooled to 0 DEG C, and be then slowly added dropwise to Grignard reagent 2 (100mL, 1M in THF), about half hour drips off, and drips off rear continuation reaction one hour.Reaction terminates to add 200mL semi-saturation aqueous ammonium chloride solution toward system, divides three aqueous phase extracted after separatory with 150mLEA, obtains crude product after merging the water washing of organic phase saturated common salt, anhydrous sodium sulfate drying through underpressure distillation.Crude product purified by silica gel column chromatography (PE: EA=20: 1) purifying, obtains compound 3 (colorless oil, 8.1g, 69%).
Get after compound 3 (4.11g, 15mmol) is dissolved in the anhydrous DCM of 200mL and be cooled to-78 DEG C, be then slowly added dropwise to MeAlCl
2(22.5mL, 1M in hexane, and dilute with 50mL DCM), within about about 80 minutes, drip off, drip off rear continuation and react one hour at-78 DEG C.Then at-78 DEG C, in system, 5mL Et is slowly added after elder generation
3n and 10mL H
2the mixed solution of O and MeOH (volume ratio 1: 4), rises to after room temperature until system and adds 120mL saturated aqueous ammonium chloride.Divide three aqueous phase extracted with 90mL DCM after separatory, after the organic phase saturated common salt water washing of merging, anhydrous sodium sulfate drying, obtain crude product through underpressure distillation.Crude product purified by silica gel column chromatography (PE: EA=5: 1) purifying, obtains product 4 (white solid, 2.8g, 68%).
1H NMR(500MHz，CDCl
3)δ6.97(d，J=8.4Hz，1H)，6.79(d，J=2.6Hz，1H)，6.67(dd，J=8.4，2.7Hz，1H)，3.77(s，3H)，3.31(dd，J=11.4，4.8Hz，1H)，3.00-2.67(m，2H)，2.28(dt，J=13.1，3.5Hz，1H)，1.93-1.67(m，4H)，1.56(td，J=13.1，4.1Hz，1H)，1.45(s，1H)，1.32(dd，J=12.3，2.3Hz，1H)，1.23-1.16(m，3H)，1.07(s，3H)，0.90(s，3H)。
13C NMR(100MHz，CDCl
3)δ157.78，150.69，129.81，127.30，111.05，110.27，78.70，55.31，49.83，39.08，37.86，37.02，29.88，28.25，28.04，24.85，19.00，15.49。
Compound 4 (548mg, 2mmol) is dissolved in the mixed solvent of 10mL DMSO and THF (volume ratio is 2: 1), adds IBX (1120mg, 4mmol), react 3 hours under normal temperature, then add 20mL water and 10mL EA, with sand core funnel filtering white solid.By 20mL EA aqueous phase extracted at twice after separatory, merge organic phase, obtain crude product with after saturated common salt water washing, anhydrous sodium sulfate drying through underpressure distillation.Crude product purified by silica gel column chromatography (PE: EA=10: 1) purifying, obtains compound 5 (white solid, 462mg, 85%).
Get compound 5 (250mg, 0.92mmol) be added in 50mL round-bottomed flask, 20mL dry toluene is added after nitrogen replacement, then NaH (183mg is added, 60%, 4.6mmol), react under normal temperature after 0.5 hour and add ethyl formate (680.8mg, 9.2mmol), reaction 2 hours is continued.Steam, except after toluene, reaction system is placed in ice bath, add 10mL frozen water, divide three aqueous phase extracted with 30mL EA.The machine merged obtains compound 6 with after saturated common salt water washing, anhydrous sodium sulfate drying through underpressure distillation mutually.Compound 6 is dissolved in 5mL Glacial acetic acid, under ice bath, adds NH
2nH
2.H
2o (280mg, 85%, 5.6mmol), reacts 6 hours under normal temperature.After reaction terminates, system 30mL EA dilutes.The saturated NaHCO of organic phase
3crude product is obtained through underpressure distillation after washing, anhydrous sodium sulfate drying.Crude product purified by silica gel column chromatography (DCM, DCM: MeOH=50: 1) purifying obtains compound 7 (faint yellow solid, 226mg, two step productive rates 83%).
1H NMR(400MHz，CDCl
3)δ7.42(s，1H)，7.03(d，J=8.4Hz，1H)，6.91(d，J=2.5Hz，1H)，6.73(dd，J=8.4，2.6Hz，1H)，3.82(s，3H)，3.15(d，J=14.9Hz，1H)，3.00-2.69(m，2H)，2.55(d，J=14.8Hz，1H)，1.95(dd，J=12.6，5.6Hz，1H)，1.87-1.66(m，2H)，1.43(s，3H)，1.34(s，3H)，1.20(s，3H)。
13C NMR(100MHz，CDCl
3)δ158.12，150.40，148.37，133.34，129.89，127.93，113.14，111.65，111.62，55.43，50.11，39.60，35.65，33.94，31.57，30.83，24.83，23.64，20.10。
Embodiment 2: the preparation of compound 24,25,26
By compound 4 (2.65g, 10.9mmol) be dissolved in the anhydrous DCM of 30ml, add diacetyl oxide (3320mg, 32.6mmol) and under DMAP (244mg, 2mmol) normal temperature react 4 hours, steaming desolventizes, with silica gel column chromatography (PE: EA=20: 1) purifying, obtain compound 8 (white solid, 2.68g, 86%).
Compound 8 (722mg, 2.28mmol) is dissolved in the anhydrous DCM of 20mL, after system being chilled to 0 DEG C, adds Aluminum chloride anhydrous (913mg, 6.84mmol), be then added dropwise to Acetyl Chloride 98Min. (358mg, 4.56mmol).Drip rear continuation to react 2 hours at 0 DEG C, add 20mL frozen water.By 30mL DCM aqueous phase extracted at twice after separatory, merge organic phase, obtain crude product with after saturated common salt water washing, anhydrous sodium sulfate drying through underpressure distillation.Crude product purified by silica gel column chromatography (PE: EA=10: 1 → 5: 1) purifying, obtains compound 9 (white solid, 666mg, 81%).
Be Material synthesis compound 10 by similar method with compound 8, productive rate 85%.
Be Material synthesis compound 11 by similar method with compound 8, productive rate 91%.
Compound 9 (413mg, 1.15mmol) is dissolved in 8ml acetic acid, N
2the Pd/C that 40mg massfraction is 4 ~ 6% is added, then H after displacement
2displacement.Reaction system is placed in 60 DEG C of oil bath reacting by heating 6 hours, reaction terminates rear 20ml EA and dilutes, and filtering solid, then washs with saturated sodium bicarbonate.Organic phase obtains crude product through underpressure distillation, obtains compound 12 (white solid, 265mg, productive rate 67%) after crude product silica gel column chromatography (PE: EA=20: 1) purifying.
By similar method, be Material synthesis compound 13 with compound 10, productive rate 45%.
By similar method, be Material synthesis compound 14 with compound 11, productive rate 78%.
Compound 12 (265mg, 0.77mmol) is dissolved in 10mL MeOH, adds NaOH (80mg, 2mmol) back flow reaction 3 hours afterwards.Steam and add water to system except after methyl alcohol, divide three aqueous phase extracted with 30mL EA.Merge organic phase, obtain compound 15 (white solid, 232mg, 95%) with underpressure distillation after saturated common salt water washing, anhydrous sodium sulfate drying.
By similar method, be Material synthesis compound 16 with compound 13, productive rate 94%.
By similar method, be Material synthesis compound 17 with compound 14, productive rate 97%.
In reference example 1 and the method for pyrazole ring, by compound 15 through 3 step Reactive Synthesis compounds 24 (faint yellow solid, three step productive rates 86%).
1H NMR(400MHz，CDCl
3)δ7.42(s，1H)，6.87(s，1H)，6.82(s，1H)，3.85(d，J=6.2Hz，3H)，3.16(d，J=14.8Hz，1H)，2.98-2.70(m，2H)，2.70-2.44(m，3H)，2.02-1.62(m，3H)，1.42(s，3H)，1.36-1.30(m，3H)，1.24-1.19(m，6H)。
13C NMR(100MHz，CDCl
3)δ156.09，150.51，145.23，133.40，130.63，129.25，127.38，113.27，107.68，55.62，50.24，39.47，35.76，33.94，31.58，30.84，24.79，23.63，22.85，20.16，14.21。
In reference example 1 and the method for pyrazole ring, by compound 16 through 3 step Reactive Synthesis compounds 25 (faint yellow solid, three step productive rates 48%).
1H NMR(400MHz，CDCl
3)δ6.81(s，1H)，6.68(s，1H)，3.78(s，3H)，2.92-2.40(m，7H)，2.03-1.86(m，2H)，1.85-1.71(m，2H)，1.38-1.20(m，14H)，1.16(s，3H)，1.13(s，3H)，0.88(t，J=6.7Hz，3H)。
13C NMR(100MHz，CDCl
3)δ156.17，150.50，145.24，133.33，130.11，129.20，127.23，113.29，107.72，55.62，50.20，39.46，35.74，33.93，32.01，31.57，30.80，24.80，23.62，23.17，20.15，14.41。
In reference example 1 and the method for pyrazole ring, by compound 17 through 3 step Reactive Synthesis compounds 26 (faint yellow solid, three step productive rates 53%).
1H NMR(400MHz，CDCl
3)δ7.43(s，1H)，6.84(d，J=12.7Hz，2H)，3.85(s，3H)，3.17(d，J=14.8Hz，1H)，3.00-2.69(m，2H)，2.66-2.46(m，3H)，1.95(dd，J=12.4，5.1Hz，1H)，1.89-1.66(m，2H)，1.63-1.52(m，2H)，1.43 (s，3H)，1.35(s，3H)，1.22(s，3H)，0.95(t，J=7.3Hz，3H)。
13C NMR(100MHz，CDCl
3)δ156.04，150.25，145.11，133.45，129.90，129.29，127.15，113.12，107.63，55.53，50.11，39.36，35.65，33.81，32.17，31.46，30.71，29.72，29.46，24.70，23.50，22.83，20.05.14.08。
Embodiment 3: the preparation of compound 36,37,38
Compound 9 (1.79g, 5mmol) is dissolved in 20mL methyl alcohol, adds NaOH (400mg, 10mmol) back flow reaction and steam methyl alcohol after 2 hours.Add water to system, divide three aqueous phase extracted with 30mL EA, merge organic phase, obtain compound 27 (white solid, 1.44g, 99%) with underpressure distillation after saturated common salt water washing, anhydrous sodium sulfate drying.
Compound 27 (950mg, 3mmol) is dissolved in 20mL MeOH, adds NaBH
4(228mg, 6mmol) reaction 3 hours under normal temperature afterwards.Steam and add water to system except after methyl alcohol, divide three aqueous phase extracted with 30mL EA, merge organic phase, obtain compound 28 (white solid, 928mg, 97%) with underpressure distillation after saturated common salt water washing, anhydrous sodium sulfate drying.
Compound 27 (1.1g, 3.48mmol) is dissolved in the anhydrous THF of 20mL, at 0 DEG C, adds CH
3mgCl (5ml, 3M in THF), then rises to room temperature reaction 6 hours naturally.Under ice bath, in system, add 30mL saturated ammonium chloride solution after reaction terminates, divide three aqueous phase extracted with 30mL EA.Merge organic phase, successively use saturated common salt water washing, anhydrous sodium sulfate drying, underpressure distillation obtains compound 29 (white solid, 1.03g, 89%).
Compound 28 (636mg, 2mmol) is dissolved in the anhydrous THF of 20mL, to add after a small amount of tosic acid back flow reaction 5 hours.Then in system, add semi-saturation sodium hydrogen carbonate solution, divide three aqueous phase extracted with 45mL EA.Merge organic phase, successively use saturated common salt water washing, anhydrous sodium sulfate drying, underpressure distillation obtains crude product.Crude product obtains compound 30 (white solid, 465mg, productive rate 77%) with after column chromatography (PE: EA=3: 1) purifying.
By similar method, be Material synthesis compound 31 with compound 29, productive rate 80%.
In reference example 1 and the method for pyrazole ring, by compound 30 through 3 step Reactive Synthesis compounds 36 (white solid, three step productive rates 45%)
1h NMR (500MHz, CDCl
3) δ 7.37 (s, 1H), 7.18 (s, 1H), 6.98 (dd, J=17.7, 11.1Hz, 1H), 6.85 (s, 1H), 5.72 (d, J=17.7Hz, 1H), 5.23 (d, J=11.2Hz, 1H), 3.85 (d, J=10.8Hz, 3H), 3.15 (d, J=14.7Hz, 1H), 2.98-2.74 (m, 2H), 2.55 (d, J=14.7Hz, 1H), 1.95 (dd, J=12.8, 5.6Hz, 1H), 1.86-1.68 (m, 2H), 1.38 (s, 3H), 1.30 (s, 3H), 1.21 (s, 3H).
13C NMR(100MHz，CDCl
3)δ155.53，150.59，147.77，133.23，131.56，127.78，126.98，125.02，114.23，113.15，108.47，55.86，50.15，39.69，35.71，33.97，31.58，30.84，24.73，23.65，20.11。
In reference example 1 and the method for pyrazole ring, by compound 31 through 3 step Reactive Synthesis compounds 37 (white solid, three step productive rates 75%)
1h NMR (400MHz, CDCl
3) δ 8.36 (br.s, 1H), 7.43 (s, 1H), 6.89 (d, J=25.5Hz, 2H), 5.11 (d, J=16.9Hz, 2H), 3.85 (s, 3H), 3.17 (d, J=14.7Hz, 1H), 2.99-2.69 (m, 2H), 2.58 (d, J=14.7Hz, 1H), 2.13 (s, 3H), 1.96 (dd, J=12.3,4.8Hz, 1H), 1.89-1.66 (m, 2H), 1.43 (s, 3H), 1.34 (s, 3H), 1.23 (s, 3H).
13C NMR(100MHz，CDCl
3)δ155.35，150.61，146.94，143.97，133.22，130.83，129.69，127.60，115.04，113.21，108.57，55.85，50.16，39.56，35.69，33.96，31.58，30.75，24.76，23.65，23.40.20.11。
Compound 37 (160mg, 0.48mmol) is dissolved in 10mL MeOH, N
2the Pd/C that 20mg massfraction is 4 ~ 6% is added, then H after displacement
2displacement, reaction overnight under normal temperature.Reaction terminates rear with being lined with diatomaceous sand core funnel suction filtration, filtering Pd/C, obtains crude product after removing solvent under reduced pressure.Compound 38 (faint yellow solid, 135mg, productive rate 83%) is obtained after crude product column chromatography (DCM: MeOH=100: 1) purifying.
1H NMR(500MHz，CDCl
3)δ7.38(s，1H)，6.90(s，1H)，6.82(s，1H)，3.84(s，3H)，3.29-3.18(m，1H)，3.14(d，J=14.7Hz，1H)，2.97-2.74(m，2H)，2.56(d，J=14.7Hz，1H)，1.94(dd，J=12.7，5.7Hz，1H)，1.84(d，J=12.6Hz，1H)，1.78-1.65(m，1H)，1.38(s，3H)，1.30(s，3H)，1.24-1.17(m，9H)。
Embodiment 4: the preparation of compound 42
Compound 4 (831mg, 3.03mmol) is dissolved in the anhydrous DCM of 80mL, after the bath of system cryosel is cooled to 0 DEG C, is slowly added dropwise to Br
2(485mg, 3.03mmol), dropwises rear continuation 0 DEG C of reaction one hour.Then the saturated aqueous solution of sodium bisulfite of 30mL is added to system, three aqueous phase extracted are divided with 30mL DCM after separatory, compound 39 (faint yellow solid, 1.07g, 100%) is obtained through underpressure distillation after the organic phase saturated common salt water washing merged, anhydrous sodium sulfate drying.
In reference example 1 and the method for pyrazole ring, by compound 39 through 3 step Reactive Synthesis compounds 42 (faint yellow solid, three step productive rates 43%).
1H NMR(400MHz，CDCl
3)δ7.60(br.s，1H)，7.43(s，1H)，7.27(s，1H)，6.87(s，1H)，3.91(d，J=6.2Hz，3H)，3.15(d，J=14.8Hz，1H)，2.96-2.69(m，2H)，2.55(d，J=14.7Hz，1H)，1.94(dd，J=12.2，5.0Hz，1H)，1.87-1.62(m，2H)，1.42(s，3H)，1.33(s，3H)，1.19(s，3H)。
13C NMR(100MHz，CDCl
3)δ154.36，150.52，147.53，133.32，133.02，129.70，112.89，109.79，109.37，56.49，49.93，39.65，35.67，33.96，31.54，30.51，24.78，23.61，19.88。
Embodiment 5: class tricyclic diterpene and the bacteriostatic activity of pyrazole derivatives test
Testing method: the bacterial classification preserved in-80 DEG C of refrigerators is activated at the flat lining out of TSA (Tryptic Soy Agar, tryptose soya agar).Next day respectively from picking staphylococcus aureus strains Newman, NRS-1, NRS-70, NRS-100, NRS-108, NRS-271 mono-clonal flat board in 10ml TSB substratum, 37 DEG C, 250rpm cultivates 12h.Be transferred in fresh TSB (Tryptic Soy Broth, trypticase soybean broth) substratum according to the ratio of 1: 1000 subsequently, 37 DEG C are cultured to A600 is 0.6 (about 2-3 hour).Bacterium liquid TSB substratum is diluted 200 times, gets in 96 orifice plates that 100 μ l add containing 100 μ l compounds.Compound is in advance with the dilution of TSB substratum equimultiple, and final concentration is 0.025-50 μ g/mL.96 orifice plates are placed in 37 DEG C of incubator static gas wave refrigerator 18h.The growing state of bacterium in each hole of visual inspection next day, using the minimum concentration of compound not bacteria growing inhibiting as the MIC value of this compound.First instance is optimized further after obtaining the approximate range of MIC within the scope of this, finally obtains best MIC value.Each sample carries out three parallel laboratory tests.
Test result: class tricyclic diterpene of the present invention pyrazole derivatives has good bacteriostatic activity, as shown in table 1.Compound 7 pairs of newman bacterial strains and NRS-1, NRS-271, NRS-70, NRS-100, NRS-108 five kinds of Resistant strain all have inhibit activities to a certain degree.After phenyl ring introducing ethyl, n-propyl, normal-butyl, the inhibition of corresponding compound 24,25,26 pairs of newman bacterial strains is remarkable, and MIC is respectively 1.25-1.5,1-1.25,1-1.25 μ g/mL; After phenyl ring introduces sec.-propyl, bromine atoms, corresponding compound 38,42 has significant inhibit activities to five kinds of drug-resistant S. aureus NRS-1, NRS-271, NRS-70, NRS-100, NRS-108 bacterial strains, and MIC is respectively 1.56-3.12,3.12-6.25,0.7-1.56,1.56-3.12,1.56-3.12 μ g/mL and 1.56-3.12,1.56-3.12,1.56-3.12,1.56-3.12,1.56-3.12 μ g/mL.Experiment shows, class tricyclic diterpene of the present invention pyrazole derivatives can be used as potential antibacterials, has applications well prospect.
Table 1: compound 7,24,25,26,36,37,38,42 is to the inhibit activities data (MIC) of different staphylococcus aureus strains
Claims (7)
1. a kind tricyclic diterpene pyrazole derivatives, it is characterized in that, its structure is such as formula shown in (I):
Wherein, R=-H ,-CH
2cH
3,-CH
2cH
2cH
3,-CH
2cH
2cH
2cH
3,-CH=CH
2,-C (CH
3)=CH
2,-CH (CH
3)
2,-Br.
2. class tricyclic diterpene as claimed in claim 1 pyrazole derivatives, is characterized in that, described class tricyclic diterpene pyrazole derivatives are respectively:
3. preparation formula (I) class tricyclic diterpene the method for pyrazole derivatives, it is characterized in that, starting compound 1 and compound 2 generate compound 3 through linked reaction under the catalysis of tetrachloro copper lithium, compound 3 is facilitated lower generation ring closure reaction in methylaluminum dichloride and is generated compound 4, compound 4 is oxidized to obtain compound 5 through IBX, compound 6 is obtained after the C-2 position formylation of compound 5, compound 6 and hydrazine hydrate are obtained by reacting formula (I) class tricyclic diterpene and pyrazole derivatives, wherein, R=-H; The reaction scheme of described preparation method is as following:
4. preparation formula (I) class tricyclic diterpene the method for pyrazole derivatives, it is characterized in that, starting compound 4 and acetic anhydride obtain compound 8, compound 8 respectively with Acetyl Chloride 98Min., propionyl chloride, butyryl chloride reacting generating compound 9, 10, 11, then compound 12 is obtained respectively through Pd/C hydrogenation, 13, 14, compound 15, 16, 17 by compound 12, 13, 14 obtain through hydrolysis reaction, then after IBX oxidation, compound 18 is obtained, 19, 20, compound 21 is reacted to obtain with ethyl formate, 22, 23, compound 21, 22, 23 react obtain formula (I) class tricyclic diterpene respectively and pyrazole derivatives with hydrazine hydrates, wherein, R is respectively-CH
2cH
3,-CH
2cH
2cH
3,-CH
2cH
2cH
2cH
3, the reaction scheme of described preparation method is as following:
5. preparation formula (I) class tricyclic diterpene the method for pyrazole derivatives, it is characterized in that, starting compound 9 obtains compound 27 through hydrolysis reaction, compound 27 obtains compound 28 with sodium borohydride and methyl chloride reactive magnesium respectively, 29, then dewater to obtain compound 30 under Catalyzed by p-Toluenesulfonic Acid, 31, compound 32, 33 by compound 30, 31 obtain through IBX oxidation, then compound 34 is reacted to obtain with ethyl formate, 35, compound 34, 35 obtain formula (I) class tricyclic diterpene and pyrazole derivatives 36 with hydrazine hydrate generation ring closure reaction respectively, 37, wherein, R is respectively-CH=CH
2,-C (CH
3)=CH
2, further, compound 37 obtains formula (I) class tricyclic diterpene and pyrazole derivatives after Pd/C hydrogenation, and wherein, R is-CH (CH
3)
2, the reaction scheme of described preparation method is as following:
6. preparation formula (I) class tricyclic diterpene the method for pyrazole derivatives, it is characterized in that, starting compound 4 and bromine react to obtain compound 39, then compound 40 is oxidized to obtain through IBX, the C-2 position of compound 40 obtains compound 41 after formylation, then be obtained by reacting formula (I) class tricyclic diterpene with hydrazine hydrate and pyrazole derivatives, wherein, R is-Br; The reaction scheme of described preparation method is as following:
7. formula (I) class tricyclic diterpene the pyrazole derivatives application in preparation antibacterials.
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| CN111362882A (en) * | 2018-12-26 | 2020-07-03 | 华东师范大学 | Tricyclic diterpene 2-methylpyrimidine analogue and preparation method and application thereof |
| CN113473983A (en) * | 2018-12-24 | 2021-10-01 | 索伦托药业有限公司 | Methods of treating parkinson's disease by administration of resiniferatoxin |
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| CN113473983A (en) * | 2018-12-24 | 2021-10-01 | 索伦托药业有限公司 | Methods of treating parkinson's disease by administration of resiniferatoxin |
| CN111362882A (en) * | 2018-12-26 | 2020-07-03 | 华东师范大学 | Tricyclic diterpene 2-methylpyrimidine analogue and preparation method and application thereof |
| CN111362882B (en) * | 2018-12-26 | 2021-12-07 | 华东师范大学 | Tricyclic diterpene 2-methylpyrimidine analogue and preparation method and application thereof |
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