CN105017155B - Class tricyclic diterpene and pyrazole derivatives and its preparation method and application - Google Patents
Class tricyclic diterpene and pyrazole derivatives and its preparation method and application Download PDFInfo
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- CN105017155B CN105017155B CN201410153124.3A CN201410153124A CN105017155B CN 105017155 B CN105017155 B CN 105017155B CN 201410153124 A CN201410153124 A CN 201410153124A CN 105017155 B CN105017155 B CN 105017155B
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- YDVPNDSGOKQDBM-NRUDEOEASA-N CC(C)C(C(CCc1c2)[C@](C)(CC3)c1cc(OC)c2C(C)=O)C3OC(C)=O Chemical compound CC(C)C(C(CCc1c2)[C@](C)(CC3)c1cc(OC)c2C(C)=O)C3OC(C)=O YDVPNDSGOKQDBM-NRUDEOEASA-N 0.000 description 1
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Abstract
The present invention relates to class tricyclic diterpene shown in a kind of formula (I) and pyrazole derivatives and preparation method thereof; compound 4 obtained and ring closure reaction with the coupled product (compound 3) of 4 methoxy-benzyl magnesium chlorides (compound 2) in geraniol epoxy acetate (compound 1) there is; its C ring (phenyl ring) introduces bromine or various alkyl substituents; A rings introduce pyrazole ring through steps such as IBX oxidations, 2 formylateds of C and pyrazole rings, obtain formula (I) class tricyclic diterpene and pyrazole derivatives.The invention also discloses the application of formula (I) such tricyclic diterpene and pyrazole derivatives in antibacterials are prepared.
Description
Technical field
The invention belongs to medicine and its technical field for preparing and applying, and in particular to simultaneously pyrazoles spreads out a species tricyclic diterpene
Biology and preparation method thereof and the application in antibacterials are prepared.
Background technology
Today's society, the excessive use of antibiotic has expedited the emergence of many endurance strains, and the resistance to the action of a drug of bacterium is considered as right
The serious threat of human health.Staphylococcus aureus (Staphylococcus aureus) is a kind of Gram-positive
Ball-type bacterium.It is in institute and one of the most popular pathogen of Nosocomial Infections, and suppuration, tympanitis, septicopyemia can be caused after infection
Disease, enteritis, nasosinusitis, osteomyelitis, the pneumonia even disease such as septicemia.There are many drug-fast changes in staphylococcus aureus
Kind, such as methicillin-resistant staphylococcus aureus (Methicillin-resistent Staphylococcus aureus,
MRSA).MRSA can resist beta-lactam, FQNS, macrolides, aminoglycoside and Tetracyclines etc. and resist
Raw element, its infection is most scabrous clinical problem in world wide.Infectd in treatment MRSA every year extra in the whole world
Spend up to hundred million dollars of 30-40 (Journal of Medicinal Chemistry, 2014,57,1609-1615).A small number of antibiosis
Element such as vancomycin (vancomycin), linezolid (Linezolid), Daptomycin (daptomycin), CPT
(ceftaroline) it is to treat the last line of defense that MRSA infects.But, occurred at present under vancomycin sensitive
The drop even staphylococcus aureus strains of resistance, also occur in that the case of linezolid and the failure of Daptomycin clinical treatment
(Journal of Medicinal Chemistry, 2013,56,3257-3272.).Natural tricyclic diterpene compound such as peach is opened up
The antibacterial activity of phenol, carnosic acid and ferruginol etc. it is verified that, but tricyclic diterpene compound is extracted from plant
Often content is few, purification difficult.Building new class tricyclic diterpene compound by the method for organic synthesis is used for antibacterials
Research and development be a kind of more efficient way.
The content of the invention
An object of the present invention is to provide a class class tricyclic diterpene and pyrazole derivatives, shown in its structure such as formula (I)：
Wherein, R=-H ,-CH2CH3、-CH2CH2CH3、-CH2CH2CH2CH3、-CH=CH2、-C(CH3)=CH2、-CH(CH3)2、-
Br。
In the present invention, distinguish corresponding class tricyclic diterpene with above-mentioned substitution base and pyrazole derivatives are：Compound 7,24,
25th, 26,36,37,38,42, its structural formula is as follows respectively.
Preparation method another object of the present invention is to provide formula (I) class tricyclic diterpene and pyrazole derivatives, geraniol
To there is cyclization in epoxy acetate (compound 1) anti-with the coupled product (compound 3) of 4- methoxy-benzyls magnesium chloride (compound 2)
Compound 4 should be obtained, its C ring (phenyl ring) introduces bromine or various alkyl substituents, A rings through IBX oxidations, C-2 formylated and pyrrole
The steps such as azoles ring introduce pyrazole ring, obtain class tricyclic diterpene shown in formula (I) and pyrazole derivatives.
The preparation method of formula (I) class tricyclic diterpene of the present invention and pyrazole derivatives includes following synthetic route：
Route 1, preparation class tricyclic diterpene and pyrazole derivatives 7
Compound 1 and compound 2 generate compound 3 under the catalysis of tetrachloro copper lithium through coupling reaction, and compound 3 is in methyl two
Aluminium chloride facilitates lower generation ring closure reaction generation compound 4, and compound 4 aoxidizes to obtain compound 5, C-2 of compound 5 through IBX
Compound 6 is obtained after formylated, compound 6 obtains class tricyclic diterpene and pyrazole derivatives 7 with hydration hydrazine reaction, wherein, R=-H.
The reaction scheme of the preparation method is for example following：
Route 2, preparation class tricyclic diterpene and pyrazole derivatives 24,25,26
Compound 4 obtains compound 8 with acetic anhydride, and compound 8 is given birth to chloroacetic chloride, propionyl chloride, butyl chloride reaction respectively
Into compound 9,10,11, then through Pd/C hydrogenations respectively compound 12,13,14, compound 15,16,17 by compound 12,
13rd, 14 obtained through hydrolysis, then through IBX aoxidize after compound 18,19,20, with Ethyl formate react compound 21,
22nd, 23, class tricyclic diterpene and pyrazole derivatives 24,25,26 are obtained with hydration hydrazine reaction by compound 21,22,23 respectively, its
In, R is respectively-CH2CH3、-CH2CH2CH3、-CH2CH2CH2CH3。
The reaction scheme of the preparation method is for example following：
Route 3, preparation class tricyclic diterpene and pyrazole derivatives 36,37,38
Compound 9 obtains compound 27 through hydrolysis, and compound 27 is obtained with sodium borohydride and methyl chloride reactive magnesium respectively
Compound 28,29, is then dehydrated to obtain compound 30,31 under Catalyzed by p-Toluenesulfonic Acid, and compound 32,33 is by compound 30,31
Obtained through IBX oxidations, compound 34,35 is then reacted to obtain with Ethyl formate, compound 34,35 occurs cyclization with hydrazine hydrate respectively
Class tricyclic diterpene and pyrazole derivatives 36,37 are reacted to obtain, wherein, R is respectively-CH=CH2、-C(CH3)=CH2。
Further, class tricyclic diterpene and pyrazole derivatives 38 are obtained after compound 37 is hydrogenated through Pd/C, wherein, R is-CH
(CH3)2。
The reaction scheme of the preparation method is for example following：
Route 4, preparation class tricyclic diterpene and pyrazole derivatives 42
Compound 4 reacts to obtain compound 39 with bromine, then aoxidizes to obtain compound 40, C-2 warp of compound 40 through IBX
Compound 41 is obtained after formylated, then class tricyclic diterpene and pyrazole derivatives 42 is obtained with hydration hydrazine reaction, wherein, R is-Br.
The reaction scheme of the preparation method is for example following：
It is all to react the performance level all reacted come tracking and measuring with TLC in preparation method of the present invention, after completion of the reaction
The post-processing approach that one is used is including suction filtration, recrystallization, extraction, distillation, column chromatography for separation etc..Final product nuclear magnetic resonance
Compose to verify.
The advantage of class tricyclic diterpene of the present invention and pyrazole derivatives and preparation method thereof includes, raw materials used cheap and easy to get,
By Li2CuCl4Coupling reaction and MeAlCl under catalysis2Ring closure reaction under catalysis efficiently constructs class tricyclic diterpene
Compound 4, phenyl ring methoxyl group ortho position introduces pyrazole ring after introducing different substituents at C-2, C-3, has synthesized a series of structures
Novel class tricyclic diterpene and pyrazole derivatives.Preparation method synthetic route of the present invention is short, reaction condition is gentle, it is environment-friendly,
Agents useful for same is cheap.
Present invention also offers the application of formula (I) class tricyclic diterpene and pyrazole derivatives in antibacterials are prepared.This hair
Simultaneously pyrazole derivatives have preferable bacteriostatic activity to bright formula (I) class tricyclic diterpene, can be used as bacteriostatic agent.The ring two of class three shown in formula (I)
Simultaneously pyrazole derivatives have preferable inhibitory activity to terpene to staphylococcus aureus newman bacterial strains, while to some antibody-resistant bacterium such as
NRS-1 bacterial strains (staphylococcus aureus of aminoglycoside-resistant antibiotic and tetracycline), NRS-271 bacterial strain (methicillin-resistants
With the staphylococcus aureus of Linezolid), NRS-70 bacterial strains (staphylococcus aureus of resistance to erythromycin and spextinomyxin),
NRS-100 bacterial strains (staphylococcus aureus of resistance to oxacillin and tetracycline), the NRS-108 bacterial strains (gold of resistance to gentamicin
Staphylococcus aureus) there is a certain degree of inhibitory activity, as shown in table 1.Wherein, 24,25,26 pairs of newman bacterial strains of compound
Inhibition significantly, MIC (minimum inhibitory concentration, minimum inhibitory concentration) is respectively 1.25-
1.5th, 1-1.25,1-1.25 μ g/mL；Compound 38 and the 42 couples of five kinds of drug-resistant S. aureus NRS-1, NRS-271,
NRS-70, NRS-100, NRS-108 bacterial strain have significant inhibitory activity, and MIC is respectively 1.56-3.12,3.12-6.25,0.7-
1.56th, 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 that simultaneously pyrazole derivatives can be used as potential antimicrobial for formula (I) class tricyclic diterpene of the present invention
Thing, with applications well prospect.
Specific embodiment
With reference to specific examples below, the present invention is described in further detail, of the invention to protect content not limit to
In following examples.Under the spirit and scope without departing substantially from inventive concept, those skilled in the art it is conceivable that change and excellent
Point is all included in the present invention, and with appending claims as protection domain.Implement process of the invention, condition,
Reagent, experimental technique etc., in addition to the following special content for referring to, are the universal knowledege and common knowledge of this area, this hair
It is bright that content is not particularly limited.In following embodiments, compound structure is by nmr determination；Reagent is main by Shanghai traditional Chinese medicines
Chemical reagents corporation provides；Mainly by column chromatography, silica gel (200-300) is produced purifying products by Haiyang Chemical Plant, Qingdao.
Embodiment 1：The preparation of compound 7
By starting compound 1 (9.04g, 42.6mmol) and Li2CuCl4(34mL, 0.1M in THF) is dissolved in 60mL THF
In, ice salt bath is cooled to 0 DEG C, is then slowly added dropwise into RMgBr 2 (100mL, 1M in THF), and about half an hour drips off, drop
Continue to react a hour after complete.Reaction terminates to add 200mL semi-saturation aqueous ammonium chloride solutions toward system, is used after point liquid
150mLEA aqueous phase extracteds in three times, obtain after merging organic phase saturated common salt water washing, anhydrous sodium sulfate drying through vacuum distillation
Crude product.Crude product purified by silica gel column chromatography (PE: EA=20: 1) is purified, and obtains compound 3 (colorless oil, 8.1g, 69%).
Take 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 into
MeAlCl2(22.5mL, 1M in hexane, and with 50mL DCM dilute), drip off within about 80 minutes or so, continue after dripping off-
A hour is reacted at 78 DEG C.Then 5mL Et are slowly added in after elder generation at -78 DEG C to system3N and 10mL H2O and MeOH
The mixed liquor of (volume ratio 1: 4), adds 120mL saturated aqueous ammonium chlorides after system is warmed to room temperature.90mL is used after dividing liquid
DCM aqueous phase extracteds in three times, obtain slightly after organic phase saturated common salt water washing, the anhydrous sodium sulfate drying of merging through vacuum distillation
Product.Crude product purified by silica gel column chromatography (PE: EA=5: 1) is purified, and obtains product 4 (white solid, 2.8g, 68%).1H NMR
(500MHz, CDCl3) δ 6.97 (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, CDCl3) δ 157.78,150.69,
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), is added
IBX (1120mg, 4mmol), is reacted 3 hours under normal temperature, is subsequently adding 20mL water and 10mL EA, and white is filtered with sand core funnel
Solid.20mL EA aqueous phase extracteds at twice are used after dividing liquid, merges organic phase, with saturated common salt water washing, anhydrous sodium sulfate drying
Crude product is obtained by vacuum distillation.Crude product purified by silica gel column chromatography (PE: EA=10: 1) purify, obtain compound 5 (white solid,
462mg, 85%).
Take compound 5 (250mg, 0.92mmol) to be added in 50mL round-bottomed flasks, 20mL is added after nitrogen displacement without water beetle
Benzene, is subsequently adding NaH (183mg, 60%, 4.6mmol), under normal temperature react 0.5 hour after add Ethyl formate (680.8mg,
9.2mmol), continue to react 2 hours.Reaction system is placed in ice bath after toluene is evaporated off, adds 10mL frozen water, use 30mL EA
Aqueous phase extracted in three times.After machine saturated common salt water washing, the anhydrous sodium sulfate drying of merging compound is obtained through vacuum distillation
6.Compound 6 is dissolved under 5mL glacial acetic acid, ice bath and adds NH2NH2.H2O (280mg, 85%, 5.6mmol), 6 are reacted under normal temperature
Hour.After reaction terminates, system is diluted with 30mL EA.Organic phase saturation NaHCO3Through subtracting after washing, anhydrous sodium sulfate drying
Pressure distills to obtain crude product.Crude product purified by silica gel column chromatography (DCM, DCM: MeOH=50: 1) purify compound 7 (faint yellow solid,
226mg, two step yields 83%).1H NMR (400MHz, CDCl3) δ 7.42 (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, CDCl3) δ 158.12,150.40,148.37,133.34,
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
Compound 4 (2.65g, 10.9mmol) is dissolved in the anhydrous DCM of 30ml, acetic anhydride (3320mg, 32.6mmol) is added
And reacted 4 hours under DMAP (244mg, 2mmol) normal temperature, solvent is evaporated off, purified with silica gel column chromatography (PE: EA=20: 1), obtain
Compound 8 (white solid, 2.68g, 86%).
Compound 8 (722mg, 2.28mmol) is dissolved in the anhydrous DCM of 20mL, system is cooled to anhydrous chlorination is added after 0 DEG C
Aluminium (913mg, 6.84mmol), is then added dropwise to chloroacetic chloride (358mg, 4.56mmol).Continue to react 2 at 0 DEG C after dripping
Hour, add 20mL frozen water.With 30mL DCM aqueous phase extracteds at twice after point liquid, merge organic phase, with saturated common salt water washing,
After anhydrous sodium sulfate drying crude product is obtained through vacuum distillation.Crude product purified by silica gel column chromatography (PE: EA=10: 1 → 5: 1) is purified,
Obtain compound 9 (white solid, 666mg, 81%).
With similar method with compound 8 for Material synthesis compound 10, yield 85%.
With similar method with compound 8 for Material synthesis compound 11, yield 91%.
Compound 9 (413mg, 1.15mmol) is dissolved in 8ml acetic acid, N2It is 4~6% that 40mg mass fractions are added after displacement
Pd/C, then H2Displacement.Reaction system is placed in into 60 DEG C of oil bath heatings to react 6 hours, reaction is dilute with 20ml EA after terminating
Release, filter solid, then washed with saturated sodium bicarbonate.Organic phase obtains crude product, crude product silica gel column chromatography through vacuum distillation
(PE: EA=20: 1) obtains compound 12 (white solid, 265mg, yield 67%) after purification.
With similar method, with compound 10 for Material synthesis compound 13, yield 45%.
With similar method, with compound 11 for Material synthesis compound 14, yield 78%.
Compound 12 (265mg, 0.77mmol) is dissolved in 10mL MeOH, adds NaOH (80mg, 2mmol) to flow back afterwards anti-
Answer 3 hours.Added water to system after methyl alcohol is evaporated off, with 30mL EA aqueous phase extracteds in three times.Merge organic phase, use saturated aqueous common salt
Vacuum distillation obtains compound 15 (white solid, 232mg, 95%) after washing, anhydrous sodium sulfate drying.
With similar method, with compound 13 for Material synthesis compound 16, yield 94%.
With similar method, with compound 14 for Material synthesis compound 17, yield 97%.
In reference implementation example 1 and pyrazole ring method, by 3 steps compound 24 is synthesized by compound 15 (faint yellow
Solid, three step yields 86%).1H NMR (400MHz, CDCl3) δ 7.42 (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, CDCl3)δ
156.09,150.51,145.23,133.40,130.63,129.25,127.38,113.27,107.68,55.62,50.24,
39.47,35.76,33.94,31.58,30.84,24.79,23.63,22.85,20.16,14.21.
In reference implementation example 1 and pyrazole ring method, by 3 steps compound 25 is synthesized by compound 16 (faint yellow
Solid, three step yields 48%).1H NMR (400MHz, CDCl3) δ 6.81 (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, CDCl3) δ 156.17,150.50,145.24,133.33,
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 implementation example 1 and pyrazole ring method, by 3 steps compound 26 is synthesized by compound 17 (faint yellow
Solid, three step yields 53%).1H NMR (400MHz, CDCl3) δ 7.43 (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, CDCl3) δ 156.04,150.25,145.11,133.45,129.90,129.29,
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 2 small
When after steam methyl alcohol.Added water to system, with 30mL EA aqueous phase extracteds in three times, merge organic phase, with saturated common salt water washing,
Vacuum distillation obtains compound 27 (white solid, 1.44g, 99%) after anhydrous sodium sulfate drying.
Compound 27 (950mg, 3mmol) is dissolved in 20mL MeOH, NaBH is added4(228mg, 6mmol) is anti-under normal temperature afterwards
Answer 3 hours.Added water to system after methyl alcohol is evaporated off, with 30mL EA aqueous phase extracteds in three times, merge organic phase, use saturated aqueous common salt
Vacuum distillation obtains compound 28 (white solid, 928mg, 97%) after washing, anhydrous sodium sulfate drying.
Compound 27 (1.1g, 3.48mmol) is dissolved in the anhydrous THF of 20mL, CH is added at 0 DEG C3MgCl (5ml, 3M in
THF), reaction 6 hours is then warmed to room temperature naturally.Reaction terminate after under ice bath to system in add 30mL saturated ammonium chlorides it is molten
Liquid, with 30mL EA aqueous phase extracteds in three times.Merge organic phase, successively with saturated common salt water washing, anhydrous sodium sulfate drying, subtract
Pressure distills to obtain compound 29 (white solid, 1.03g, 89%).
Compound 28 (636mg, 2mmol) is dissolved in the anhydrous THF of 20mL, adds back flow reaction after a small amount of p-methyl benzenesulfonic acid
5 hours.Then to semi-saturation sodium bicarbonate solution is added in system, with 45mL EA aqueous phase extracteds in three times.Merge organic phase,
Successively with saturated common salt water washing, anhydrous sodium sulfate drying, vacuum distillation obtains crude product.Crude product with column chromatography (PE: EA=3:
1) compound 30 (white solid, 465mg, yield 77%) is obtained after purification.
With similar method, with compound 29 for Material synthesis compound 31, yield 80%.
In reference implementation example 1 and pyrazole ring method, (white is solid by 3 steps compound 36 to be synthesized by compound 30
Body, three step yields 45%)1H NMR (500MHz, CDCl3) 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, CDCl3) δ 155.53,150.59,147.77,133.23,131.56,127.78,126.98,125.02,
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 implementation example 1 and pyrazole ring method, (white is solid by 3 steps compound 37 to be synthesized by compound 31
Body, three step yields 75%)1H NMR (400MHz, CDCl3) 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, CDCl3) δ 155.35,150.61,146.94,143.97,
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, N2Added after displacement 20mg mass fractions be 4~
6% Pd/C, then H2Displacement, reaction overnight under normal temperature.React after terminating with diatomaceous sand core funnel suction filtration is lined with, filter
Pd/C, crude product is obtained after removing solvent under reduced pressure.It is (yellowish that crude product column chromatography (DCM: MeOH=100: 1) obtains compound 38 after purification
Color solid, 135mg, yield 83%).1H NMR (500MHz, CDCl3) δ 7.38 (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, is delayed after system ice salt bath is cooled into 0 DEG C
Slowly it is added dropwise to Br2(485mg, 3.03mmol), continues to react a hour at 0 DEG C after completion of dropping.Then added to system
30mL saturation aqueous solution of sodium bisulfite, uses 30mL DCM aqueous phase extracteds in three times, the organic phase of merging to be eaten with saturation after point liquid
After salt water washing, anhydrous sodium sulfate drying compound 39 (faint yellow solid, 1.07g, 100%) is obtained through vacuum distillation.
In reference implementation example 1 and pyrazole ring method, by 3 steps compound 42 is synthesized by compound 39 (faint yellow
Solid, three step yields 43%).1H NMR (400MHz, CDCl3) δ 7.60 (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, CDCl3) δ 154.36,150.52,147.53,133.32,133.02,129.70,
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：The bacteriostatic activity test of class tricyclic diterpene and pyrazole derivatives
Method of testing：The strain that will be preserved in -80 DEG C of refrigerators is in TSA (Tryptic Soy Agar, Triptic soya fine jade
Fat) flat lining out activation.Next day respectively from flat board picking staphylococcus aureus strains Newman, NRS-1, NRS-70,
In 10ml TSB culture mediums, 37 DEG C, 250rpm cultivates 12h to NRS-100, NRS-108, NRS-271 monoclonal.Then according to 1:
1000 ratio is transferred in fresh TSB (Tryptic Soy Broth, trypticase soybean broth) culture medium, 37 DEG C of cultures
It is 0.6 (about 2-3 hours) to A600.Bacterium solution is diluted 200 times with TSB culture mediums, 100 μ l is taken and is added containing 100 μ l compounds
96 orifice plates in.Compound is diluted with TSB culture mediums equimultiple in advance, final concentration of 0.025-50 μ g/mL.96 orifice plates are placed in 37
Static gas wave refrigerator 18h in DEG C incubator.Next day visually observes the growing state of bacterium in each hole, does not suppress bacterium life with compound
Least concentration long as the compound MIC value.After first instance obtains the approximate range of MIC, within the range further
Optimization, finally gives optimal MIC value.Each sample carries out three parallel laboratory tests.
Test result：Simultaneously pyrazole derivatives have preferable bacteriostatic activity to class tricyclic diterpene of the present invention, as shown in table 1.Chemical combination
Thing 7 has certain journey to five kinds of antibody-resistant bacterium of newman bacterial strains and NRS-1, NRS-271, NRS-70, NRS-100, NRS-108
The inhibitory activity of degree.Phenyl ring introduces correspondence 24,25,26 suppression pair newman bacterial strains of compound after ethyl, n-propyl, normal-butyl
Effect is significant, MIC is respectively 1.25-1.5,1-1.25,1-1.25 μ g/mL；Phenyl ring introduces correspondence chemical combination after isopropyl, bromine atoms
38,42 pairs of five kinds of drug-resistant S. aureus NRS-1, NRS-271, NRS-70, NRS-100, NRS-108 bacterial strains of thing have aobvious
The inhibitory activity of work, MIC be respectively 1.56-3.12,3.12-6.25,0.7-1.56,1.56-3.12,1.56-3.12 μ g/mL with
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 of the present invention three
Simultaneously pyrazole derivatives can be as potential antibacterials, with applications well prospect for ring diterpene.
Table 1：The inhibitory activity number of the different staphylococcus aureus strains of compound 7,24,25,26,36,37,38,42 pairs
According to (MIC)
Claims (6)
1. a species tricyclic diterpene and pyrazole derivatives, it is characterised in that shown in its structure such as formula (I)：
Wherein, R=-H ,-CH2CH3、-CH2CH2CH3、-CH2CH2CH2CH3,-CH=CH2、-C(CH3)=CH2、-CH(CH3)2、-
Br。
2. the method that one kind prepares formula as claimed in claim 1 (I) class tricyclic diterpene and pyrazole derivatives, it is characterised in that
Starting compound 1 and compound 2 generate compound 3 under the catalysis of tetrachloro copper lithium through coupling reaction, and compound 3 is in methyl dichloro
Aluminium facilitates lower generation ring closure reaction generation compound 4, and compound 4 aoxidizes to obtain compound 5, C-2 formyl of compound 5 through IBX
Compound 6 is obtained after change, compound 6 obtains formula (I) class tricyclic diterpene and pyrazole derivatives with hydration hydrazine reaction, wherein, R=-H；
The reaction scheme of the preparation method is for example following：
3. the method that one kind prepares formula as claimed in claim 1 (I) class tricyclic diterpene and pyrazole derivatives, it is characterised in that
Starting compound 4 obtains compound 8 with acetic anhydride, and compound 8 reacts generationization with chloroacetic chloride, propionyl chloride, butyl chloride respectively
Compound 9,10,11, then obtains compound 12,13,14 respectively through Pd/C hydrogenations, and compound 15,16,17 is by compound 12,13,14
Obtained through hydrolysis, then through IBX aoxidize after compound 18,19,20, with Ethyl formate react compound 21,22,
23, compound 21,22,23 respectively obtains formula (I) class tricyclic diterpene and pyrazole derivatives with hydration hydrazine reaction, wherein, R difference
For-CH2CH3、-CH2CH2CH3、-CH2CH2CH2CH3；The reaction scheme of the preparation method is for example following：
4. the method that one kind prepares formula as claimed in claim 1 (I) class tricyclic diterpene and pyrazole derivatives, it is characterised in that
Starting compound 9 obtains compound 27 through hydrolysis, and compound 27 obtains chemical combination with sodium borohydride and methyl chloride reactive magnesium respectively
Thing 28,29, is then dehydrated to obtain compound 30,31 under Catalyzed by p-Toluenesulfonic Acid, and compound 32,33 is by compound 30,31 through IBX
Oxidation is obtained, and compound 34,35 is then reacted to obtain with Ethyl formate, and compound 34,35 occurs ring closure reaction with hydrazine hydrate respectively
Formula (I) class tricyclic diterpene and pyrazole derivatives 36,37 are obtained, wherein, R is respectively-CH=CH2、-C(CH3)=CH2；Further
Ground, compound 37 obtains formula (I) class tricyclic diterpene and pyrazole derivatives after being hydrogenated through Pd/C, wherein, R is-CH (CH3)2；It is described
The reaction scheme of preparation method is for example following：
5. the method that one kind prepares formula as claimed in claim 1 (I) class tricyclic diterpene and pyrazole derivatives, it is characterised in that
Starting compound 4 and bromine react to obtain compound 39, then aoxidize to obtain compound 40 through IBX, and C-2 of compound 40 through formyl
Compound 41 is obtained after change, then formula (I) class tricyclic diterpene and pyrazole derivatives is obtained with hydration hydrazine reaction, wherein, R is-Br；Institute
The reaction scheme for stating preparation method is for example following：
6. the application of formula (I) class tricyclic diterpene as claimed in claim 1 and pyrazole derivatives in antibacterials are prepared.
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| Potential anti-inflammatory diterpenes from Premna obtusifolia;A.-W. Salae et al.;《Tetrahedron》;20111127;第68卷;819-829 * |
| Syntheses and Antibacterial Activities of Diterpene Catechol Derivatives with Abietane, Totarane and Podocarpane Skeletons against Methicillin-Resistant Staphylococcus aureus and Propionibacterium acnes;Masahiro TADA等;《Chem. Pharm. Bull.》;20100315;第58卷(第6期);818-824 * |
| Synthesis of Variously Oxidized Abietane Diterpenes and Their Antibacterial Activities Against MRSA and VRE;Zhixiang Yang等;《Bioorg.Med.Chem.》;20011231;第9卷(第2期);347-356 * |
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