CN102285886A - (+)-2-bornyl chlorobenzoate and preparation method and use thereof - Google Patents
(+)-2-bornyl chlorobenzoate and preparation method and use thereof Download PDFInfo
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- CN102285886A CN102285886A CN2011101636839A CN201110163683A CN102285886A CN 102285886 A CN102285886 A CN 102285886A CN 2011101636839 A CN2011101636839 A CN 2011101636839A CN 201110163683 A CN201110163683 A CN 201110163683A CN 102285886 A CN102285886 A CN 102285886A
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- borneol
- bornyl
- chloro
- norbornene ester
- benzoic acid
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Abstract
The invention relates to bornyl benzoate. The chemical structure of the bornyl benzoate is represented by a formula (I) below, and the chemical name of the bornyl benzoate is (+)-2-bornyl chlorobenzoate. The synthesis method of the bornyl benzoate is to add (+)-borneol, 2-chlorobenzoic acid in an amount which is 1.04 times the mass of borneol and p-methyl-benzenesulfonic acid in an amount which is 0.067 times that of borneol into toluene to react at 110 DEG C for 6 hours. The (+)-2-bornyl chlorobenzoate has low toxicity and a blood brain barrier permeating effect and can promote medicines to permeate blood brain barriers.
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-inflammatories, analgesic activity; 2 antibiotic and antivirus actions; 3 antifertility actions.
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.
Summary of the invention
The derivative that the purpose of this invention is to provide a kind of borneol, this derivative significantly improves than the ability of the saturating hemato encephalic barrier of borneol.
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 (+)-2-chloro-benzoic acid borneol fat.
(+) of the present invention-2-chloro-benzoic acid borneol fat adopts this area common method synthetic, as, (+)-borneol and 2-chloro-benzoic 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: 1.04 times 2-chloro-benzoic acid of (+)-borneol, borneol quality and 0.067 times p-methyl benzenesulfonic acid of borneol quality are added in the toluene, and reaction got final product in 6 hours under 110 ℃.
Compound exhibits of the present invention goes out better saturating hemato encephalic barrier effect, 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 (+)-2-chloro-benzoic acid norbornene ester
Add 150g natural Broneolum Syntheticum, 156g 2-chloro-benzoic acid and 500ml toluene in the 1000ml round-bottomed flask; Drip the 10g p-methyl benzenesulfonic acid, mix; Under 110 ℃, reacted 6 hours.Remove catalyzer after the reaction, unreacted 2-chloro-benzoic acid and solvent obtain head product.Head product obtains white crystals with ethyl alcohol recrystallization.
2. the character of (+)-2-chloro-benzoic acid norbornene ester
The white crystals that step l obtains is insoluble in water, dissolves in acetone, ethyl acetate, ethanol, methyl alcohol.Fusing point is 41.4～42.2 ℃.
3. the evaluation of compound of the present invention:
1. ultimate analysis: ultimate analysis (%): measured value C69.70, H7.20 calculated value C69.73, H7.23.
2. 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: CD
3OD.
13CNMR(400Hz，CD
3OD/TMS，δ，ppm)：14.07，19.3，20.2，28.4，29.0，37.8，46.3，48.6，49.5，83.0，128.0，130.7，132.2，133.1，133.7，134.0，167.7。The solvent peak deuterated methanol appears near 49.0.
1HNMR (400Hz, CD
3OD/TMS, δ, ppm): 0.913 (6H, s, 2CH
3), 0.955 (3H, s, CH
3), 1.088-1.140 (1H, m, CH
2), 1.251-1.287 (1H, m, CH
2), 1.293-1.368 (2H, m, CH
2), 1.713-1.810 (1H, m, CH), 2.125-2.173 (1H, m, CH), 2.421-2.488 (2H, t, CH
2), 3.872 (3H, s, OCH
3), 5.083-5.104 (1H, m, CH), 7.431 (1H, d, phenyl ring), 7.563-7.621 (2H, m, phenyl ring), 8.161 (1H, d, phenyl ring).The solvent peak deuterated methanol appears near 3.33 (methyl) and 4.87 (hydroxyls).
3. 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 1722 (ester, C=O), 1377 (s, CH
3), strong the absorption appears in the methyl stretching vibration.1278 (ester, C-O), 1122 (ester, C-O), 755 ((s, phenyl ring C-H), the strong absorption appears in the C-H stretching vibration, demonstrates the characteristics of ortho position substituted benzene.
4.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; It is 292. that sweep limit: m/z20-500 analyzes the molecular weight of determining this compound
The mensuration of 5 specific rotatioies:
Instrument: Perkin Eimer 341 automatic polarimeters
The preparation of liquid to be measured: precision takes by weighing about 25.9mg (+)-2-chloro-benzoic acid norbornene ester and places the 50ml 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 (+)-2-chloro-benzoic 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 (+)-O-Anisic 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.
1.3. 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 maximum drug tolerance test of the single of (+)-2-chloro-benzoic acid norbornene ester
Undertaken by " Chinese medicine, natural drug studies on acute toxicity technical director principle " method.20 of Kunming kind small white mouses are divided into 2 groups (control group, medicine groups), 10 every group at random by body weight.Gavage administration suspension with 0.5%CMC-Na preparation (+)-2-chloro-benzoic acid norbornene ester peak concentration.According to the mouse body weight, the medicine group gavages-norbornene ester 0.5% tween 20 suspension by 0.8ml/20g dosage, and control group gavages equal-volume 0.5% tween 20.Observe acute toxic reaction behind the medicine, comprise animal behavior, activity, eyelid, hair, secretory product, abdomen shape and ight soil etc.Observe 3-4h behind the medicine continuously, observe every day thereafter 1 time, observed continuously 7 days.
2.1. the maximum drug tolerance experimental observation of single result
Mouse does not have the performance of acute toxicities such as restlessness, expiratory dyspnea, convulsions, tachycardia, vomiting after the administration, and the part mouse show of short duration shock, dull, be slow in action, symptom such as perpendicular tail, recover normal but above-mentioned symptom is basic behind 2-5min.
2.2. mouse body weight change
Its body weight of record before and after the mouse gavaging norbornene ester 0.5% tween 20 suspension the results are shown in Table 3 through the t check, the mouse gavaging norbornene ester with gavage solvent ratio than there was no significant difference (p＞0.05).
Body weight before and after the table 3 mouse gavaging norbornene ester
With the contrast of 0.5% tween 20 group, * p＞0.05.
The maximum drug tolerance test-results of mouse single shows, 2-chloro-benzoic acid norbornene ester maximum tolerated dose is 19.00g/kg, can think (+)-2-chloro-benzoic acid norbornene ester toxicity is low, belongs to the lower toxicity material, gavage (+)-the mouse normal growth cycle is not had influence behind the 2-chloro-benzoic acid norbornene ester.
Embodiment 3
The saturating hemato encephalic barrier effect experiment of (+)-2-chloro-benzoic acid norbornene ester
Animal subject: Kunming mouse, body weight 18-23g, male and female half and half.
Experimental technique: Kunming mouse is divided into two groups at random, 4 of blank groups, 12 of test group, experiment fasting in eve.According to the mouse body weight, press the suspension of 1.5g/kg dosage preparation 2-chloro-benzoic acid norbornene ester and 0.5% (v/v) tween.Blank group, test group mouse gavage the suspension of 0.5% (v/v) tween liquid, 2-chloro-benzoic acid norbornene ester and 0.5% (v/v) tween respectively by 0.4ml/20g (body weight).Each organize mouse after perfusion 25min by 10ml/kg (body weight) tail vein injection 0.4%0.5% (m/m) 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, add acetone-physiological saline (volume ratio 7: 3) homogenate by 1: 8 (weightmeasurement ratio) after weighing in cerebral tissue, homogenate is hatched 0.5h, the centrifugal 15min of 3000r/min in 70 ℃, get supernatant liquor and measure absorbancy in the 620nm place, the results are shown in Table 4
Table 4 (+)-saturating hemato encephalic barrier effect of 2-chloro-benzoic acid norbornene ester experimental result
With solvent control group ratio
*P＜0.01 is with dextrorotation borneol group ratio
#P＜0.05
Experimental result shows that (+)-2-chloro-benzoic acid norbornene ester and blank group relatively have the barrier action of significant penetration rate of blood brain; Compare with dextrorotation borneol group, its saturating hemato encephalic barrier effect obviously is better than the dextrorotation borneol.
Embodiment 4
Prescription: (+)-2-chloro-benzoic 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 (+)-2-chloro-benzoic 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 (+)-2-chloro-benzoic 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 made up of following steps: 1.04 times 2-chloro-benzoic acid of (+)-borneol, borneol quality and 0.067 times p-methyl benzenesulfonic acid of borneol quality are added in the toluene, and reaction got final product in 6 hours under 110 ℃.
3. the described a kind of phenylformic acid norbornene ester of claim 1 promotes medicine to penetrate the application in the hemato encephalic barrier medicine 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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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 |
Non-Patent Citations (1)
| Title |
|---|
| 陈瑞玉等: "天然冰片及其结构修饰物对惊厥模型小鼠氨基酸类神经递质的影响", 《中药新药与临床药理》, no. 03, 31 May 2011 (2011-05-31), pages 283 - 284 * |
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: 20111221 |