CN102276469A - (+)-4-methoxy bornyl benzoate as well as preparation method and application thereof - Google Patents
(+)-4-methoxy bornyl benzoate as well as preparation method and application thereof Download PDFInfo
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- CN102276469A CN102276469A CN2011101473225A CN201110147322A CN102276469A CN 102276469 A CN102276469 A CN 102276469A CN 2011101473225 A CN2011101473225 A CN 2011101473225A CN 201110147322 A CN201110147322 A CN 201110147322A CN 102276469 A CN102276469 A CN 102276469A
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- borneol
- methoxybenzoic acid
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- norbornene ester
- bornyl
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Abstract
The invention relates to bornyl benzoate as well as a preparation method and application thereof. The bornyl benzoate has the chemical structure shown in a formula (I) as the specification, and has the chemical name of (+)-4-methoxy bornyl benzoate. The synthesis method of the bornyl benzoate in the invention comprises the steps of: adding (+)-borneol, 4-methoxybenzoic acid and p-tolenesulfonic acid into toluene, reacting at 120 DEG C for 8h to obtain the bornyl benzoate, wherein the 4-methoxybenzoic acid is 0.75 time that of the borneol in weight, and p-tolenesulfonic acid is 0.025 time that of the borneol in weight. The (+)-4-methoxy bornyl benzoate in the invention has low cytotoxicity and a blood-brain barrier permeating function and can promote medicaments to permeate through a blood-brain barrier.
Description
Technical field
The present invention relates to benzoic ether, be specifically related to contain the benzoic ether of six-ring.
Background technology
Borneol is an adjutant commonly used simply in the Chinese materia medica.The traditional Chinese medical science thinks that it has the effect of the inducing resuscitation of having one's ideas straightened out, clearing away heat to and alleviating pain, myogenic, is widely used in coma and closes card by each doctor family from ancient times, closes with controlling in pyreticosis coma, the phlegm heat, acute diseases such as hot summer weather is finally fainted, infantile convulsion.Its main pharmacological comprises 1, anti-inflammatory, analgesic activity; 2, antibiotic and antivirus action; 3, antifertility action.
Modern medicine study shows that it is loose that borneol can obviously make the hemato encephalic barrier iuntercellular closely connect, and the transhipment of material intercellular channel is quickened; Borneol can obviously make the hemato encephalic barrier cell gulp down drink vesicle quantity to increase, and volume increases, thereby the substance transportation that gulps down drink through cell is quickened.But the ability of the saturating hemato encephalic barrier of borneol is still not ideal enough.In addition, borneol also has certain genotoxicity, limits its application.
Summary of the invention
The derivative that the purpose of this invention is to provide a kind of borneol, this derivative is low than borneol toxicity, and the ability of saturating hemato encephalic barrier significantly improves.
The technical scheme that the present invention addresses the above problem is:
A kind of phenylformic acid norbornene ester, its structural formula are shown in (I):
The chemical name of phenylformic acid norbornene ester shown in the following formula (I) is (+)-4-methoxybenzoic acid borneol fat.
(+) of the present invention-4-methoxybenzoic acid borneol fat adopts this area common method synthetic, as, (+)-borneol and 4-methoxybenzoic acid are carried out esterification obtain under the p-methyl benzenesulfonic acid katalysis.The method that the inventor recommends is made up of following steps: 0.75 times 4-methoxybenzoic acid of (+)-borneol, borneol quality, 0.025 times p-methyl benzenesulfonic acid of borneol quality added in the toluene, reacted 8 hours down at 120 ℃, both.
Compound of the present invention has the characteristics of low cytotoxicity, and demonstrates better saturating hemato encephalic barrier effect than borneol, can be applied as preparation and promote to penetrate the hemato encephalic barrier medicine.
Embodiment
With specific embodiment preparation method of the present invention and effect thereof are described in further detail below.
Embodiment 1
1. synthesizing of (+)-4-methoxybenzoic acid norbornene ester
Add 20g natural Broneolum Syntheticum, 15g 4-methoxybenzoic acid and 30ml toluene in the 500ml round-bottomed flask; Drip the 0.5g p-methyl benzenesulfonic acid, mix; Under 120 ℃, stirring and refluxing 8 hours.Remove catalyzer after the reaction, unreacted borneol and solvent obtain head product.Head product obtains colourless crystallization with the silicagel column separation.
2. the character of (+)-4-methoxybenzoic acid norbornene ester
The colourless crystallization that step 1 obtains is insoluble in water, is soluble in chloroform, ethanol, acetone, ethyl acetate.Fusing point is 66.3-68.6 ℃.
3. the evaluation of compound of the present invention:
1.UV atlas analysis: invent described compound dissolve with methanol, use PDA-100 diode-array detector (DAD) scanning then, this compound has uv-absorbing at 212.3nm, 259.0nm wavelength place.
2.MS atlas analysis:, adopt the ionization method analysis: the EI source with day island proper Tianjin mass spectrometer; Sample introduction temperature: 250 ℃; Column temperature: 200 ℃; Gas: nitrogen; Electronic attack source: 70eV; Sweep limit: m/z20-300.Analyzing the molecular weight of determining this compound is 288.15.
3. nuclear magnetic resonance spectrum map analysis: German Bruker 500MHz nuclear magnetic resonance analyser, model AV-500; Probe: 5mmBBOBB-1H; Pulse: zg30 (hydrogen spectrum), zgdc30 (carbon spectrum); Solvent: CDCl
3
13CNMR(500Hz，CDCl
3/TMS，6，ppm，)：13.59，18.90，19.71，27.40，28.05，36.92，45.00，47.83，49.05，55.37，80.07，113.54，123.37，131.49，163.21，166.51。
1HNMR (500Hz, CDCl
3/ TMS, 6, ppm): 0.920 (6H, s, 2CH
3), 0.962 (3H, s, CH
3), 1.093-1.127 (1H, m, CH
2), 1.279-1.331 (1H, m, CH
2), 1.368-1.419 (2H, m, CH
2), 1.724-1.825 (1H, m, CH), 2.104-2.157 (1H, m, CH), 2.428-2.490 (2H, t, CH
2), 3.854 (3H, s, OCH
3), 5.078-5.109 (1H, m, CH), 6.914-6.931 (2H, d, phenyl ring), 7.954-7.963 (2H, d, phenyl ring).The solvent peak deuterochloroform appears at 7.26.
4. infrared spectra spectrum analysis: detecting instrument: FI-IR EQUINOX 55 Bruker (Germany); Testing conditions: KBr compressing tablet; Detect foundation: GB/T 6040-2002 infrared spectrum analysis general rule.
IR (KBr compressing tablet) v/cm
-1: characteristic peak 1703 (ester, C=O), 1301 (s, CH
3), the methyl stretching vibration occurs absorbing 1283 by force, and (ester, C-O), 1119 (ester, C-O), 773 (s, C-H), the strong absorption appears in the C-H stretching vibration, demonstrates the characteristics of para-orientation benzene.
5. the mensuration of specific rotatory power:
Instrument: Perkin Eimer 341 automatic polarimeters
The preparation of liquid to be measured: precision takes by weighing about 10mg (+)-4-methoxybenzoic acid norbornene ester and places the 10ml measuring bottle, with anhydrous alcohol solution and be diluted to scale, and even shaking.
Measuring method: behind the liquid washing sample pipe to be measured 2-3 time, liquid to be measured is injected sample hose, put into the sample chamber by same position and direction, build case lid, dial produces the specific rotation of this sample automatically.Duplicate reading is averaged and is made the sample determination result.
The calculation result of measurement result and specific rotatory power sees Table 1.
The specific rotatory power of table 1 (+)-4-methoxybenzoic acid norbornene ester (589nm, 20 ℃)
Have opticity by the visible compound of the present invention of table 1, and be single dextrorotation.
The compound of above-mentioned detected result confirmation step 1 preparation is (+)-4-methoxybenzoic acid norbornene ester.
Embodiment 2
1. the anxious poison test of dextrorotation borneol mouse
1.1. laboratory animal
60 of Kunming kind small white mouses, male and female half and half, body weight 20 ± 2g.Conformity certification number is provided by Guangdong Province's Experimental Animal Center: 2008-0001 Guangdong, the SCXK Guangdong word 2007A013 that checks and affirm is used for test after adapting to 3d.
1.2. experimental technique
Mouse overnight fast 15h before the administration freely drinks water.Be divided into 6 groups, 10 every group, the 1st～5 group gives the dextrorotation borneol and is in harmonious proportion fluid, and dosage is respectively 6170,4319,3023,2116,1481mg/kg; The 6th group is the solvent control group, gavages mixed oil.According to the mouse body weight, the medicine group gavages the dextrorotation borneol by 0.2mL/10g dosage, and control group gavages the equal-volume edible oil.2h recovers normal raising after the administration, observes continuously 14 days, observes the mouse body weight change every day, has or not death, and situations such as diet, activity, hair color, drainage and toxic reaction are in time dissected postmortem to dead mouse, and observing its major organs has no abnormal.All the other mouse are dissected after the observation period finishes, and observing its major organs has no abnormal.
3. experimental result
Death condition behind the mouse stomach dextrorotation borneol sees Table 2.
Table 2 dextrorotation borneol mouse stomach medium lethal dose result
LD
50Be 2425.9mg/kg, 95% credibility interval is 1939.5mg/kg～2940.6mg/kg
2. the anxious poison test of (+)-4-methoxybenzoic acid norbornene ester mouse
2.1. laboratory animal
50 of Kunming kind small white mouses, male and female half and half, body weight 20 ± 2g.Conformity certification number is provided by Guangdong Province's Experimental Animal Center: 2008-0001 Guangdong, the SCXK Guangdong word 2007A013 that checks and affirm is used for test after adapting to 3d.
2.2. experimental technique
Mouse overnight fast 15h before the administration freely drinks water.Be divided into 5 groups, 10 every group, be divided into control group and administration group.The administration group is configured to (+)-4-methoxybenzoic acid norbornene ester of series concentration with edible oil.(+)-4-methoxybenzoic acid norbornene ester dosage group was successively decreased with 1: 0.8 in scope, and promptly dosage is 5g/kg, 4g/kg, 3.2g/kg, 2.56g/kg.According to the mouse body weight, the medicine group gavages the anisic acid norbornene ester by 0.2ml/10g dosage, and control group gavages the equal-volume edible oil.2h recovers normal raising after the administration, observes continuously 14 days, observes the mouse body weight change every day, has or not death, and situations such as diet, activity, hair color, drainage and toxic reaction are in time dissected postmortem to dead mouse, and observing its major organs has no abnormal.All the other mouse are dissected after the observation period finishes, and observing its major organs has no abnormal.
2.3. experimental result
Death condition behind mouse stomach (+)-4-methoxybenzoic acid norbornene ester sees Table 3.
Table 3 (+)-4-methoxybenzoic acid norbornene ester mouse stomach medium lethal dose result
According to table 2 data, as follows with Bilss method result calculated:
Regression equation y (Probit)=0.098263+8.6979Log (D)
Medium lethal dose LD
50=3.6606g/kg
LD
50Fiducial limit=the 3.1895--4.2376g/kg of (Feiller correction) 95%
LD
5＝2.3683g/kg
LD
95＝5.658g/kg
The result shows: (+)-4-methoxybenzoic acid norbornene ester mouse stomach medium lethal dose (LD
50) be 3660.6mg/kg, meet low toxicity standard (501.00-5000.0mg/kg is a low toxicity compounds).The LD of dextrorotation borneol
50Be 2425.9mg/kg, illustrate (+)-toxicity of 4-methoxybenzoic acid norbornene ester is less than the dextrorotation borneol.
Embodiment 3
The saturating hemato encephalic barrier experimental study of (+)-4-methoxybenzoic acid norbornene ester
1. animal subject: SPF level Kunming mouse, male and female half and half, body weight 20 ± 2g.Department of Health of Guangdong Province's Experimental Animal Center provides, conformity certification number: SCXK Guangdong 2008-0002 is used for test after adapting to 3d.Kunming mouse overnight fasting 15h before the administration freely drinks water.
2. method
2.1 soup preparation
Precision takes by weighing the 40mg Azo-Blue and gets and be transferred in the 10ml volumetric flask, adds physiological saline and is settled to scale marks and promptly gets 0.4% solution; Acetone and physiological saline mixing (7: 3) (v: v) promptly get the mixed solution that is used for homogenate.
2.2 the blue typical curve of ivens is drawn
Doubly release series concentration solution 0.5ug/g, 10ug/g, 20ug/g, 50ug/g, 100ug/g with blank mouse brains preparation Evans Blue, detect absorbancy in the 620nm place with ultraviolet spectrophotometer.
2.3 saturating hemato encephalic barrier effect experiment: Kunming mouse is divided into 3 groups at random, 10 every group.Be divided into the solvent control group, dextrorotation borneol group and (+)-4-methoxybenzoic acid norbornene ester group.According to the mouse body weight, borneol group and (+)-4-methoxybenzoic acid norbornene ester group are pressed 1mmol/kg dosage gastric infusion, and the solvent control group is irritated the solvent of stomach equal volume.Each organize mouse after perfusion 60min by 10ml/kg (body weight) tail vein injection 0.4% Azo-Blue solution, broken end is got brain behind the 2min, cerebral tissue with a small amount of normal saline flushing after, blot with filter paper, weigh the back in cerebral tissue by 1: 8 (w: v) add acetone-physiological saline (7: 3) (v: v) homogenate, homogenate is hatched 0.5h in 70 ℃, and the centrifugal 15min of 3000r/min gets supernatant liquor 1mL and measures absorbancy in the 620nm place.
3 results
3.1 saturating hemato encephalic barrier effect experimental result
Ask according to Beer-Lambert law and absorbancy, brain weight and to calculate relative average content of dispersion in the unit cerebral tissue, the results are shown in Table 4. and obtain canonical plotting: y=0.0055x+0.0408, R
2=0.9915.
Table 4 (+)-saturating hemato encephalic barrier effect of 4-methoxybenzoic acid norbornene ester experimental result (
N=10)
With solvent control group ratio
*P＜0.05 is with dextrorotation borneol group ratio
#P＜0.05
Experimental result shows that (+)-4-methoxybenzoic acid norbornene ester and blank group relatively have significant open hemato encephalic barrier effect; Compare with dextrorotation borneol group, its saturating hemato encephalic barrier effect obviously is better than the dextrorotation borneol.
Embodiment 4
Prescription: (+)-4-methoxybenzoic acid norbornene ester 40g Microcrystalline Cellulose 54g
Starch 56g micropowder silica gel 4.5g
Croscarmellose sodium (CCNa) 4.5g sodium lauryl sulphate 0.8g
Method for making: taking by weighing (+)-4-methoxybenzoic acid norbornene ester and various auxiliary material by prescription, is tamanori with the 5%PVP-60% ethanolic soln, granulates with the sulfuration bed, and compressing tablet promptly.Make 400 altogether, every 0.4g, every contains (+)-4-methoxybenzoic acid norbornene ester 100mg.
Claims (3)
1. phenylformic acid norbornene ester, its chemical structure is as shown in the formula shown in (I):
2. the preparation method of the described a kind of phenylformic acid norbornene ester of claim 1, this method is that 0.75 times 4-methoxybenzoic acid of (+)-borneol, borneol quality, borneol quality 0.025 times p-methyl benzenesulfonic acid is added in the toluene, 120 ℃ down reaction obtaining in 8 hours.
3. the described a kind of phenylformic acid norbornene ester of claim 1 promotes medicine to penetrate the application in the medicine of hemato encephalic barrier in preparation.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106866419A (en) * | 2017-04-14 | 2017-06-20 | 石河子大学 | One terpenoid ester compounds and its production and use |
| CN107619376A (en) * | 2017-11-09 | 2018-01-23 | 宁波职业技术学院 | A kind of valine norbornene ester and its preparation method and application |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101607907A (en) * | 2009-06-22 | 2009-12-23 | 西北大学 | The benzoic acid derivative and the preparation method and use thereof that replace |
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- 2011-06-02 CN CN2011101473225A patent/CN102276469A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101607907A (en) * | 2009-06-22 | 2009-12-23 | 西北大学 | The benzoic acid derivative and the preparation method and use thereof that replace |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106866419A (en) * | 2017-04-14 | 2017-06-20 | 石河子大学 | One terpenoid ester compounds and its production and use |
| CN107619376A (en) * | 2017-11-09 | 2018-01-23 | 宁波职业技术学院 | A kind of valine norbornene ester and its preparation method and application |
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Application publication date: 20111214 |