CN102964321B - Nepetalactone fluorobenzoate, preparation technology and usage thereof - Google Patents
Nepetalactone fluorobenzoate, preparation technology and usage thereof Download PDFInfo
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- CN102964321B CN102964321B CN201210508922.4A CN201210508922A CN102964321B CN 102964321 B CN102964321 B CN 102964321B CN 201210508922 A CN201210508922 A CN 201210508922A CN 102964321 B CN102964321 B CN 102964321B
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Abstract
The invention discloses a nepetalactone fluorobenzoate, a preparation technology and the usage of the nepetalactone fluorobenzoate. The nepetalactone fluorobenzoate is characterized by having the molecular formula of C17H17FO4, the melting point of 158-160 DEG C and the specific rotation of [alpha]D<20>=+13.2 degrees (c 1.0, CH3OH). The invention also discloses an extraction method of the nepetalactone fluorobenzoate and the application of the nepetalactone fluorobenzoate in the preparation of medicine for resisting influenza virus.
Description
Technical field
The present invention relates to a kind of Schizonepetolactone fluorobenzoate and preparation technology and purposes, belong to technical field of medicine.
Background technology
Schizonepetolactone (C
10h
14o
3) for by extracting a kind of Loliolide obtaining in Chinese medicinal materials schizonepeta, be colourless grain brilliant (ethyl acetate), mp:188～189 DEG C.TLC aobvious red (10% sulfuric acid ethanol), molecular formula is C
10h
14o
3, its structural formula is
Chinese patent CN01108186.4 has disclosed structure collection of illustrative plates of Schizonepetolactone and uses thereof, it can be used for preparing anti-cold medicine, anti-inflammation drugs, antibacterials, analgesic agent etc., Chinese patent CN201010217622.1 has disclosed the one of Schizonepetolactone and has improved preparation technology, and preparation manipulation simplification, yield raising, the production cost of Schizonepetolactone are reduced.But Schizonepetolactone in vitro infected by influenza reactive force a little less than, in order to obtain the medicine of stronger resisiting influenza virus effect, intend by structure of modification, there is the sick active Schizonepetolactone derivative of stronger In Vitro Anti influenza to obtain.But up to now, not yet there is report after fluorobenzoic acid esterification, to be obtained Schizonepetolactone fluorobenzoate by Schizonepetolactone.
Summary of the invention
The object of the present invention is to provide a kind of Schizonepetolactone fluorobenzoate and its preparation method and purposes as medicine of being obtained by Schizonepetolactone after fluorobenzoic acid esterification.
Technical scheme of the present invention is as following
Schizonepetolactone fluorobenzoate, is characterized in that molecular formula is C
17h
17fO
4, fusing point is 158-160 DEG C, its specific optical rotation is=+ 13.2 ° of (c 1.0, CH
3oH), its structural formula is as follows, the temporary called after Schizonepetolactone of inventor fluorobenzoate:
Schizonepetolactone fluorobenzoate preparation method of the present invention comprises the steps:
A. get Schizonepetolactone, m-fluorobenzoic acid and DMAP (english abbreviation is DMAP) are appropriate, these three kinds of material amount of substance ratios are 0.5～1.5:1.5～2.5:0.5～1.5, be placed in reaction vessel, add methylene dichloride, stirring is dissolved it completely, add N, N'-dicyclohexylcarbodiimide (DCC) or 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride (english abbreviation is EDCI), these two kinds of material amount of substances are 1.5～2.5 times of Schizonepetolactone, in room temperature reaction, TLC checks reaction end, obtains reaction solution;
B. by A step gained reaction solution, drip methyl alcohol and make solution clarification, add silica gel, underpressure distillation solvent, to dry, obtains silica gel compound sample;
C. silica obtained B step compound sample dress post is carried out to column chromatography, the petroleum ether-ethyl acetate that is 4～7:1 with volume proportion carries out wash-out, stream part that collection contains Schizonepetolactone fluorobenzoate, reclaim under reduced pressure elutriant after merging, can obtain Schizonepetolactone fluorobenzoate white crystalline powder.
The preparation method of Schizonepetolactone fluorobenzoate in above-mentioned steps A, Schizonepetolactone, three kinds of material amount of substance ratios of m-fluorobenzoic acid and DMAP are 1:2:1; The N adding, N'-dicyclohexylcarbodiimide or 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride, these two kinds of material amount of substances are 2 times of Schizonepetolactone; The volume proportion of step C PetroChina Company Limited. ether-ethyl acetate is 5:1.
The In Vitro Anti influenza virus pharmacodynamics test of Schizonepetolactone fluorobenzoate shows, it has good anti-H
3n
2activity, therefore can be used for preparing anti-influenza virus medicament.
Schizonepetolactone fluorobenzoate of the present invention is a kind of new menthane type monoterpenes compound, and simple in structure, preparation method is easy to be inexpensive, and has stronger physiologically active.
Brief description of the drawings
Fig. 1 is the ultraviolet spectrogram of compound Schizonepetolactone fluorobenzoate, λ max (CH
3oH): 227.6nm, prompting compound has conjugation Absorption Characteristics.
Fig. 2 is the HPLC purity collection of illustrative plates of compound Schizonepetolactone fluorobenzoate, and it is 96.2% that normalization method calculates Schizonepetolactone parabromobenzoic acid ester purity.
Embodiment
Form by the following examples, Schizonepetolactone fluorobenzoate the present invention relates to and preparation method thereof is described in further detail, but this should be interpreted as to the scope of the above-mentioned theme of the present invention only limits to following example, all technology realizing based on foregoing of the present invention all belong to scope of the present invention.
Embodiment 1: take the Schizonepetolactone (method disclosing according to Chinese patent CN201010217622.1, adopt labiate schizonepeta Schizonepeta tenuifolia Briq. flower fringe to obtain through oxidation preparation with the commercially available Herba Schizonepetae volatile oil of extraction by steam distillation gained, purity is more than 98%) 18.2mg (0.10mmol), m-fluorobenzoic acid 35.1mg (0.25mmol, domestic AR level), DMAP 12.3mg (0.10mmol, domestic AR level), be placed in 50mL round-bottomed flask, add 4mL methylene dichloride (domestic AR level), stirring is dissolved it completely, add DCC 51.6mg (0.25mmol, domestic AR level), react in room temperature (20-25 DEG C), TLC checks reaction end.After reaction finishes, drip methyl alcohol (domestic AR level) and make solution clarification, add the about 500mg of triplication silica gel (Haiyang Chemical Plant, Qingdao produces, and column chromatography is used), underpressure distillation solvent is to dry.Take 5g silica gel dress post, eluent (sherwood oil (60-90 DEG C, domestic AR level): ethyl acetate (domestic AR level)=5:1) wash-out, when wash-out 40mL the left and right, TLC follows the tracks of can find target compound Schizonepetolactone fluorobenzoate, now collect elutriant, every 5mL collects once,, TLC follows the tracks of and finds target compound wash-out substantially completely when about 30mL the left and right, merge elutriant, reclaim under reduced pressure elutriant, can obtain Schizonepetolactone fluorobenzoate white crystalline powder, purity is more than 96%, yield 87%.
Embodiment 2:
The Schizonepetolactone fluorobenzoate structure elucidation that embodiment 1 prepares:
HR-ES IMS:m/z 305.1454[M+H]
+(calculated value C
17h
17fO
4for: 304.3123);
(c 1.0, CH
3oH).
IR (KBr compressing tablet, cm
-1): 3070(v
Ф-H); 2931,2848(saturated cyclic hydrocarbons v
cH); Ester carbonyl group v in 1704(
c=O); 1655(conjugation carbonyl v
c=O); 1606,1551,1505,1454(conjugation phenyl ring v
c=C); Between 899,795,691(phenyl ring, position replaces γ
Ф-H).
UV (CH
3oH) λ max:227.6nm, prompting compound has conjugation Absorption Characteristics.See accompanying drawing 1
H
1-NMR(300MHz,CDCl
3,ppm):δ1.04(d,3H,J=6.6Hz,6’-CH3),1.07(dd,1H,J=4.2,13.2Hz,5a-H),1.29(m,1H,4a-H),1.91(s,3H,3’-H),1.94-2.03(m,2H,5b-H,6-H),2.23(m,1H,4b-H),2.78-2.87(m,2H,7H),7.28-7.79(m,4H,Ar-H)。
13C-NMR(75MHz,CDCl
3,ppm):δ171.3(C-8),164.1(C-7’),162.6(C-3),160.8(C-1’),132.3,130.2(C-2’,C-6’),127.8,125.5(C-3’,C-5’),123.3(C-4’),116.7(C-7),104.5(C-4),45.1(C-5),34.5(C-1),28.9(C6),24.3(C-2),20.9(C-10),8.3(C-9)。
Schizonepetolactone fluorobenzoate purity: utilize HPLC method to detect, Schizonepetolactone fluorobenzoate peak area is 7802336, and impurity total peak area is 306852, adopting normalization method to calculate Schizonepetolactone fluorobenzoate purity is 96.2%.See accompanying drawing 2
Embodiment 3: take the Schizonepetolactone (method disclosing according to Chinese patent CN201010217622.1, adopt labiate schizonepeta Schizonepeta tenuifolia Briq. flower fringe to obtain through oxidation preparation with the commercially available Herba Schizonepetae volatile oil of extraction by steam distillation gained, purity is more than 98%) 18.2mg (0.10mmol), m-fluorobenzoic acid 35.1mg (0.25mmol, domestic AR level), DMAP 12.3mg (0.10mmol, domestic AR level), be placed in 50mL round-bottomed flask, add 4mL methylene dichloride (domestic AR level), stirring is dissolved it completely, add EDCI 46mg (0.24mmol, domestic AR level), react in room temperature (20-25 DEG C), TLC checks reaction end.After reaction finishes, drip methyl alcohol (domestic AR level) and make solution clarification, add the about 500mg of triplication silica gel (Haiyang Chemical Plant, Qingdao produces, and column chromatography is used), underpressure distillation solvent is to dry.Take 5g silica gel dress post, eluent (sherwood oil (60-90 DEG C, domestic AR level): ethyl acetate (domestic AR level)=5:1) wash-out, when wash-out 40mL the left and right, TLC follows the tracks of can find target compound Schizonepetolactone fluorobenzoate, now collect elutriant, every 5mL collects once,, TLC follows the tracks of and finds target compound wash-out substantially completely when about 30mL the left and right, merge elutriant, reclaim under reduced pressure elutriant, can obtain Schizonepetolactone fluorobenzoate white crystalline powder, purity is more than 97%, yield 84%.
Embodiment 4: take the Schizonepetolactone (method disclosing according to Chinese patent CN201010217622.1, adopt labiate schizonepeta Schizonepeta tenuifolia Briq. flower fringe to obtain through oxidation preparation with the commercially available Herba Schizonepetae volatile oil of extraction by steam distillation gained, purity is more than 98%) 24.3mg (0.15mmol), m-fluorobenzoic acid 44.8mg (0.32mmol, domestic AR level), DMAP18.5mg (0.15mmol, domestic AR level), be placed in 50mL round-bottomed flask, add 4mL methylene dichloride (domestic AR level), stirring is dissolved it completely, add DCC 66.1mg (0.32mmol, domestic AR level), react in room temperature (20-25 DEG C), TLC checks reaction end.After reaction finishes, drip methyl alcohol (domestic AR level) and make solution clarification, add the about 550mg of triplication silica gel (Haiyang Chemical Plant, Qingdao produces, and column chromatography is used), underpressure distillation solvent is to dry.Take 5g silica gel dress post, eluent (sherwood oil (60-90 DEG C, domestic AR level): ethyl acetate (domestic AR level)=6:1) wash-out, when wash-out 45mL the left and right, TLC follows the tracks of can find target compound Schizonepetolactone fluorobenzoate, now collect elutriant, every 5mL collects once,, TLC follows the tracks of and finds target compound wash-out substantially completely when about 35mL the left and right, merge elutriant, reclaim under reduced pressure elutriant, can obtain Schizonepetolactone fluorobenzoate white crystalline powder, purity is more than 97%, yield 88%.
Embodiment 5: take the Schizonepetolactone (method disclosing according to Chinese patent CN201010217622.1, adopt labiate schizonepeta Schizonepeta tenuifolia Briq. flower fringe to obtain through oxidation preparation with the commercially available Herba Schizonepetae volatile oil of extraction by steam distillation gained, purity is more than 98%) 24.3mg (0.15mmol), m-fluorobenzoic acid 44.8mg (0.32mmol, domestic AR level), DMAP 18.5mg (0.15mmol, domestic AR level), be placed in 50mL round-bottomed flask, add 4mL methylene dichloride (domestic AR level), stirring is dissolved it completely, add EDCI61.3mg (0.32mmol, domestic AR level), react in room temperature (20-25 DEG C), TLC checks reaction end.After reaction finishes, drip methyl alcohol (domestic AR level) and make solution clarification, add the about 550mg of triplication silica gel (Haiyang Chemical Plant, Qingdao produces, and column chromatography is used), underpressure distillation solvent is to dry.Take 5g silica gel dress post, eluent (sherwood oil (60-90 DEG C, domestic AR level): ethyl acetate (domestic AR level)=6:1) wash-out, when wash-out 45mL the left and right, TLC follows the tracks of can find target compound Schizonepetolactone fluorobenzoate, now collect elutriant, every 5mL collects once,, TLC follows the tracks of and finds target compound wash-out substantially completely when about 35mL the left and right, merge elutriant, reclaim under reduced pressure elutriant, can obtain Schizonepetolactone fluorobenzoate white crystalline powder, purity is more than 97%, yield 83%.
Embodiment 6: take the Schizonepetolactone (method disclosing according to Chinese patent CN201010217622.1, adopt labiate schizonepeta Schizonepeta tenuifolia Briq. flower fringe to obtain through oxidation preparation with the commercially available Herba Schizonepetae volatile oil of extraction by steam distillation gained, purity is more than 98%) 36.5mg (0.20mmol), m-fluorobenzoic acid 53.2mg (0.38mmol, domestic AR level), DMAP 24.5mg (0.20mmol, domestic AR level), be placed in 50mL round-bottomed flask, add 5mL methylene dichloride (domestic AR level), stirring is dissolved it completely, add DCC 78.5mg (0.38mmol, domestic AR level), react in room temperature (20-25 DEG C), TLC checks reaction end.After reaction finishes, drip methyl alcohol (domestic AR level) and make solution clarification, add the about 600mg of triplication silica gel (Haiyang Chemical Plant, Qingdao produces, and column chromatography is used), underpressure distillation solvent is to dry.Take 6g silica gel dress post, eluent (sherwood oil (60-90 DEG C, domestic AR level): ethyl acetate (domestic AR level)=7:1) wash-out, when wash-out 50mL the left and right, TLC follows the tracks of can find target compound Schizonepetolactone fluorobenzoate, now collect elutriant, every 5mL collects once,, TLC follows the tracks of and finds target compound wash-out substantially completely when about 40mL the left and right, merge elutriant, reclaim under reduced pressure elutriant, can obtain Schizonepetolactone fluorobenzoate white crystalline powder, purity is more than 97%, yield 86%.
Embodiment 7: take the Schizonepetolactone (method disclosing according to Chinese patent CN201010217622.1, adopt labiate schizonepeta Schizonepeta tenuifolia Briq. flower fringe to obtain through oxidation preparation with the commercially available Herba Schizonepetae volatile oil of extraction by steam distillation gained, purity is more than 98%) 36.5mg (0.20mmol), m-fluorobenzoic acid 53.2mg (0.38mmol, domestic AR level), DMAP 24.5mg (0.20mmol, domestic AR level), be placed in 50mL round-bottomed flask, add 5mL methylene dichloride (domestic AR level), stirring is dissolved it completely, add EDCI 72.8mg (0.38mmol, domestic AR level), react in room temperature (20-25 DEG C), TLC checks reaction end.After reaction finishes, drip methyl alcohol (domestic AR level) and make solution clarification, add the about 600mg of triplication silica gel (Haiyang Chemical Plant, Qingdao produces, and column chromatography is used), underpressure distillation solvent is to dry.Take 6g silica gel dress post, eluent (sherwood oil (60-90 DEG C, domestic AR level): ethyl acetate (domestic AR level)=7:1) wash-out, when wash-out 50mL the left and right, TLC follows the tracks of can find target compound Schizonepetolactone fluorobenzoate, now collect elutriant, every 5mL collects once,, TLC follows the tracks of and finds target compound wash-out substantially completely when about 40mL the left and right, merge elutriant, reclaim under reduced pressure elutriant, can obtain Schizonepetolactone fluorobenzoate white crystalline powder, purity is more than 97%, yield 85%.
The anti-H of embodiment 8 Schizonepetolactone fluorobenzoates
3n
2virus function
1 virus titer (TCID
50) mensuration
The preparation of 1.1 influenza viruses
Utilize chick embryo allantoic cavity inoculation method to prepare influenza virus, results allantoic fluid, measure viral existence by hemagglutination test (HA test), after packing-70 DEG C frozen.
The dilution of 1.2 viruses
Get the frozen viral allantoic fluid of a pipe, 1:10 dilution.
The virus liquid that the first round adds 146 μ L 1:10 to dilute, then does serial log10 dilution, makes it to become 10
-1, 10
-2, 10
-3... 10
-10.100 μ L virus liquids are contained in every hole, and each extent of dilution is inoculated a tandem totally 8 holes.
The preparation of 1.3MDCK cell and the mensuration of virus titer
Use mdck cell 1:10 was gone down to posterity in first 2 days, make it 70%～90% in blocks, discard cell culture fluid, wash cell once with 5mLEDTA-pancreatin, then discard.4mL-5mL EDTA pancreatin is covered to thin (162cm
2tissue Culture Flask) digest 10min～20min in 37 DEG C of incubators.In the time that cell starts to come off, add 5mL～10mL mdck cell nutrient solution, piping and druming cell dispersion also proceeds to centrifuge tube by cell, and the centrifugal 5min of 2000r/min, with PBS washing 2 times, to remove bovine serum.Cell suspension, in 1mL viral dilution liquid, is is fully blown and beaten to cell dispersion with suction pipe, add viral dilution liquid to 10mL, by cell counting count board counting cells quantity.Cell dilution is become to 1.5 × 10 with viral dilution liquid
5cell/mL, adds 100 μ L cells (1.5 × 10
4/ hole) in the good viral Microtitration plates of dilution.If two tandems are made in normal cell contrast, at 37 DEG C, 5%CO
2in incubator, cultivate, observe 7 days and record result.
Press Reed-Muench Liang Shi method and calculate TCID
50
2 sample cell toxicity tests
The preparation of 2.1 sample concentrations
Prepare sample by above-described embodiment 1 method, be first mixed with 20mg/mL with methyl-sulphoxide.Then using mdck cell maintenance medium (not containing the cell culture fluid of serum) to dilute is respectively 200 μ g/mL, 100 μ g/mL, 50 μ g/mL, 25 μ g/mL, 12.5 μ g/mL, 6.25 μ g/mL, 3.125 μ g/mL, 1.562 μ g/mL.
2.2 toxotest
Mdck cell is 37 DEG C of 96 well culture plate monolayer culture, and 5%CO2 cultivates 24 hours, inhales and abandons supernatant liquor, adds respectively different concns liquid, 4 holes, and every hole adds liquid 100 μ L.Through 72 hours observation of cell forms, calculate medicine and cause cell half toxicity T C
50.
3 cytopathic effect inhibition tests
Mdck cell is at 37 DEG C of 96 well culture plate monolayer culture, 5%CO
2cultivate 24 hours, inhale and abandon supernatant liquor, cell washs through diluent, and every hole adds washings 100 μ L, inhales and abandons washings, adds 30TCID
50virus liquid, 37 DEG C, 5%CO
2adsorb 2 hours, suck virus, add liquid under maximal non-toxic concentration, 4 holes, every hole dosing 100 μ L.Through 37 DEG C, 5%CO
2cultivate 72 hours, observe CPE(pathology), establish cell control group, virus control group, positive controls (ribavirin) and medicine group are observed CPE simultaneously, calculate IC
50(half effective inhibition concentration) and therapeutic index TI value.
4 results
Compound Schizonepetolactone fluorobenzoate shows good anti-H
3n
2activity, IC
50be 10.53 μ g/mL, TC
50be 29.33 μ g/mL, TI is 2.78.Under similarity condition, Schizonepetolactone does not show good anti-H
3n
2activity, therefore, Schizonepetolactone fluorobenzoate has the anti-H that is significantly better than Schizonepetolactone in vitro
3n
2active.In table 1.
Table 1 Schizonepetolactone fluorobenzoate In Vitro Anti H
3n
2active
Note: "-" represents that sample is at TC
50concentration lower time has no maybe will not be detected viral inhibition.
TI=TC
50/IC
50。
Claims (2)
1. the application of Schizonepetolactone fluorobenzoate in the anti-H3N2 influenza virus medicine of preparation, is characterized in that Schizonepetolactone fluorobenzoate, has following structure:
Preparation method comprises the steps:
A. get Schizonepetolactone, m-fluorobenzoic acid and DMAP are appropriate, and these three kinds of material amount of substance ratios are 0.5～1.5:1.5～2.5:0.5～1.5, are placed in reaction vessel, add methylene dichloride, stirring is dissolved it completely, adds N, N'-dicyclohexylcarbodiimide or 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride, these two kinds of material amount of substances are 1.5～2.5 times of Schizonepetolactone, in room temperature reaction, TLC checks reaction end, obtains reaction solution;
B. by A step gained reaction solution, drip methyl alcohol and make solution clarification, add silica gel, underpressure distillation solvent, to dry, obtains silica gel compound sample;
C. silica obtained B step compound sample dress post is carried out to column chromatography, the petroleum ether-ethyl acetate that is 4～7:1 with volume proportion carries out wash-out, stream part that collection contains Schizonepetolactone fluorobenzoate, reclaim under reduced pressure elutriant after merging, can obtain Schizonepetolactone fluorobenzoate white crystalline powder.
2. the application of Schizonepetolactone fluorobenzoate as claimed in claim 1 in the anti-H3N2 influenza virus medicine of preparation, is characterized in that Schizonepetolactone in preparation method's steps A, and three kinds of material amount of substance ratios of m-fluorobenzoic acid and DMAP are 1:2:1; The N adding, N'-dicyclohexylcarbodiimide or 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride, these two kinds of material amount of substances are 2 times of Schizonepetolactone; The volume proportion of step C PetroChina Company Limited. ether-ethyl acetate is 5:1.
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